Acylation through Ketene Intermediates
established by comparison with the NMR and IR spectra
reported in the literature.
flash chromatography (10% ethyl acetate-40-60 petroleum
ether) to give the title compound (0.160 g, 0.53 mmol, 53%),
1H NMR (300 MHz): 1.05 (d, J ) 6.8 Hz, 12H), 1.63 (s, 12H),
2.45 (dd of septets, J ) 1.4, 6.6, 6.6 Hz, 2H), 5.70 (dd, J )
15.7, 1.4 Hz, 1H), 6.84 (dd, J ) 6.6, 15.7 Hz, 1H). IR: 1653,
1718 (br), 2871, 2930, 2967, 3007 cm-1. Anal. Calcd for
P r ep a r a tion of ter t-Bu tyl Dieth ylp h osp h on oa cete (2)
th r ou gh th e Mixed An h yd r id es Meth od . To the solution
of diethylphosphonoacetic acid (196 mg, 1 mmol) and tert-butyl
alcohol (74 mg, 1 mmol) in dichloromethane (5 mL) at 0 °C
was added diphenylchlorophosphate 3a (292 mg, 1 mmol) and
triethylamine (202 mg, 2 mmol). The reaction mixture was
stirred for 20 min and dissolved in ethyl acetate (30 mL), and
the solution was washed with 5% HCl water solution, satu-
rated NaHCO3 solution, and brine, dried, and evaporated to
give ester 2 as the only reaction product (160 mg, 0.63 mmol,
63%)
C
18H30O4: C, 69.67; H, 9.68. Found: C, 70.05; H, 9.42. Further
elution provided monoalkylated product 9a (0.079 g, 0.37
mmol, 37%).
Di-ter t-bu tyl Ma lon a te (13). To a solution of malonic acid
(1.06 g, 10 mmol) and tert-butyl alcohol (1.44 g, 20 mmol) in
acetonitrile (30 mL) was added a solution of DCC (4.12 g, 20
mmol) in acetonitrile (20 mL). The reaction mixture was
stirred for 20 min, filtered, and evaporated. The residue was
bulb-to-bulb distilled in a Kugelrohr apparatus to give title
product 13 (1.96 g, 9.1 mmol, 91%); all data are identical to a
commercial sample.
The same reaction was performed with acetyl 3b and phenyl
acetyl chloride 3c instead of 3a , providing the title product
with 60 and 61% yields correspondingly. No traces of tert-butyl
1
phenyl acetate impurities were found in 300 MHz H NMR of
ter t-Bu tyl Ma lon a te (14a ). To a solution of malonic acid
(1.06 g, 10 mmol) and tert-butyl alcohol (1.44 g, 20 mmol) in
acetonitrile (30 mL) was added a solution of DCC (227 mg, 11
mmol) in acetonitrile (11 mL). The reaction mixture was
stirred for 20 min, filtered, and evaporated. The residue was
dissolved in ether (50 mL), and the ether layer was extracted
with saturated NaHCO3 solution (2 × 20 mL). The water
solution was acidified to pH 1 by 10% HCl solution and
extracted with ethyl acetate (2 × 35 mL). The ethyl acetate
solution was dried and evaporated to give the title product
(1.17 g, 7.3 mmol, 73%). Evaporation of the ether solution gave
di-tert-butyl malonate (0.20 g, 0.9 mmol, 9%).
p-Meth oxyben zyl Ma lon a te (14b). To a solution of ma-
lonic acid (424 mg, 4 mmol) and p-methoxybenzyl alcohol (552
mg, 4 mmol) in acetonitrile (24 mL) was added a solution of
DCC (9.06 g, 4.4 mmol) in acetonitrile (4.4 mL). The reaction
mixture was stirred for 10 min at room temperature, filtered,
and evaporated. The residue was dissolved in EtOAc (50 mL),
and the organic layer was extracted with saturated NaHCO3
solution (4 × 25 mL). The water solution was immediately
acidified by a saturated solution of NaH2PO4 (100 mL) and
then to pH 3 by a 10% HCl solution and extracted with ethyl
acetate (3 × 25 mL). The ethyl acetate solution was dried and
evaporated to give the pure title product (0.639 g, 2.8 mmol,
71%); all data are identical to literature.
Kin etic Stu d ies. The kinetic data were measured in the
reaction of 4-methoxybenzyl malonate (10 mM in dichlo-
romethane) with tert-butyl alcohol (10-60 mM) and DCC (10-
40 mM) at 0.4 °C. The reaction was quenched at 30-480 s
intervals with 1 mL of methanol. One milliliter samples were
filtered and dissolved in CDCl3 followed by the 300 MHz 1H
NMR analysis. Conversion was measured by the integration
of the peak belonging to tert-butyl group of the product (4-
methoxybenzyl tert-butyl malonate) vs peaks of the methyl
group of the quenching product (4-methoxybenzyl methyl
malonate).
The individual sample of p-methoxybenzyl tert-butyl mal-
onate was prepared from p-methoxybenzyl malonate (14b ),
tert-butyl alcohol, and DCC using the general procedure for
the preparation of esters 11a -d . 1H NMR (300 MHz): 1.42
(s, 9H), 3.30 (s, 2H), 3.83 (s, 3H), 5.11 (s, 2H), 6.89 (dd, J )
1.2, 8.7 Hz, 2H), 7.30 (d, J ) 1.5 Hz, 8.7 Hz, 2H). IR (film).
Anal. Calcd for C15H20O5: C, 64.28; H, 7.14. Found: C, 64.40;
H, 7.30. The individual sample of known p-methoxybenzyl
methyl malonate was prepared from p-methoxybenzyl mal-
onate 14b, methanol, and DCC using the general procedure
for the preparation of esters 11a -d .
the product.
4,8-D i m e t h y l-4-[(p h e n y ls u lfo n y l)m e t h y l]-2,3-d i -
oxa b icyclo[3.3.1]n on -8-yl 2-(Diet h oxyp h osp h or yl) Ac-
eta te (6). To a solution of alcohol 5 (55 mg, 0.17 mmol) in
dichloromethane (0.5 mL) were added diethylphosphonoacetic
acid (0.19 mL of a 1 M solution in dichloromethane, 0.19 mmol)
and DCC (0.19 mL of a 1 M solution in dichloromethane, 0.19
mmol). The reaction mixture was stirred for 15 min, filtered
through a sintered glass, and evaporated. The residue was
purified by flash chromatography (50-70% ethyl acetate-40-
60 petroleum ether) to give the title compound (80 mg, 0.16
mmol, 92%). 1H NMR (300 MHz): 1.23 (t, 6H, J ) 7.1 Hz),
1.59 (s, 3H), 1.81 (s, 3H), 1.91-2.14 (m, 7H), 2.91 (d, 2H, J )
21.6 Hz), 3.03, 3.33 (2 × d, 2H; J ) 4.1 Hz), 4.16 (app quintet,
4H, J ) 7 Hz), 4.39 (br d, 1H, J ) 3.6 Hz), 7.58 (dt, 2H, J )
1.5, 6.9 Hz), 7.67 (dt, 1H, J ) 1.2, 8.1 Hz), 7.92 (br d, 2H, J )
7.5 Hz). Anal. Calcd for C21H31O9PS: C, 52.37; H, 6.59.
Found: C, 51.96; H, 6.61.
4-Meth ylp en t-2-en oic Acid 2-Hyd r oxy-1,1,2-tr im eth yl-
p r op yl Ester (9a ). To the solution of pinacol (118 mg, 1 mmol)
and diethylphosphonoacetic acid (196 mg, 1 mmol) in THF (5
mL) was added a solution of DCC (227 mg, 1.1 mmol) in THF
(1.1 mL). The reaction mixture was stirred for 10 min at room
temperature, and filtered, the filtrate was cooled to 0 °C, and
isobutyraldehyde (144 mg, 2 mmol) and a solution of t-BuOLi
(prepared by mixing of a solution of tert-butyl alcohol (81 mg,
1.1 mmol) in THF (5 mL) with a solution of BuLi in hexanes
(0.45 mL of 2.5 M solution)) were subsequently added through
a syringe. The reaction mixture was stirred 30 min at 0 °C
and evaporated, and the residue was dissolved in ethyl acetate
(30 mL). The ethyl acetate solution was washed with saturated
NaHCO3 (3 × 20 mL) and brine, dried, and evaporated. The
residue was purified by flash chromatography (10% ethyl
acetate-40-60 petroleum ether) to give the title compound
1
(0.125 g, 0.58 mmol, 58%). H NMR (300 MHz): 1.05 (d, J )
6.8 Hz, 6H), 1.21 (s, 6H), 1.50 (s, 6H), 2.45 (dd of septets, J )
1.5, 6.8, 6.8 Hz, 1H), 3.78 (s, 1H), 5.73 (dd, J ) 16.0, 1.5 Hz,
1H), 6.89 (dd, J ) 6.8, 16.0 Hz, 1H). IR: 1652, 1715 (br), 2873,
2984, 3447 (br) cm-1. Anal. Calcd for C12H22O3: C, 66.67; H,
11.11. Found: C, 66.92; H, 10.73.
4-Meth ylp en t-2-en oic Acid 1,1,2-Tr im eth yl-2-[(4-m eth -
ylp en t-2-en oyl)oxy]p r op yl Ester (9b). To the solution of
pinacol (118 mg, 1 mmol) and diethylphosphonoacetic acid (392
mg, 2 mmol) in THF (10 mL) was added a solution of DCC
(2.5 mmol) in THF (2.5 mL). The reaction mixture was stirred
for 10 min at room temperature and filtered, the filtrate was
cooled to 0 °C, and isobutyraldehyde (288 mg, 4 mmol) and a
solution of t-BuOLi (prepared by mixing of a solution of tert-
butyl alcohol (185 mg, 2.5 mmol) in THF (10 mL) with a
solution of BuLi in hexanes (1 mL of 2.5 M solution)) were
subsequently added through a syringe. The reaction mixture
was stirred 30 min at 0 °C and evaporated, and the residue
was dissolved in ethyl acetate (30 mL). The ethyl acetate
solution was washed with satuarted NaHCO3 (3 × 20 mL) and
brine, dried, and evaporated. The residue was separated by
3-Cycloh exyl-2-(cycloh exylim in o)-6-eth oxy-5-m eth yl-
2H -1,3-oxa zin -4(3H )-on e (18). To a solution of monoethyl
2-methylmalonate (10a ) in dichloromethane (1 mL of 1M
solution) was added a solution of DCC in dichloromethane (2
mL of a 1 M solution). The reaction mixture was stirred for 1
h at room temperature, filtered through a sintered glass, and
evaporated. The residue was purified by flash chromatography
(40-60 petroleum ether-ethyl acetate 25:1) to give the title
J . Org. Chem, Vol. 67, No. 25, 2002 8981