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M. Kotke, P. R. Schreiner / Tetrahedron 62 (2006) 434–439
p-toluenesulfonic acid monohydrate (150 mg) was stirred in
an argon atmosphere at room temperature for 24 h (ketones
were refluxed for 12 h). The acid was neutralized by
dropwise addition of a saturated aqueous solution of sodium
carbonate, the organic layer was separated und washed with
an aqueous solution of sodium hydrogen sulfite (5 mL,
20%), and dried over sodium sulfate. After evaporation of
the solvent the crude product was distilled over a 10 cm
Vigreux column (in case of benzaldehyde 2 a 20 cm column
was used) under reduced pressure to furnish the pure acetals
in yields ranging from 64–81%.
was washed with water (2!15 mL) and dried over
anhydrous Na2SO4. After evaporation of the solvent in a
rotary evaporator under reduced pressure the crude products
were purified by vacuum destillation over a 10 cm Vigreux
column to afford colorless liquids; the yields ranged from
67 to 85%. Spectral data were identical to those reported
in the literature.
The acid-labile aldehyde 14 incorporating the TBDMS-
group was prepared by a straightforward literature
procedure (yield:79%).19
4.5. Synthesis of dipropyl and diisopropyl acetal of 4
4.7. Analytical methodology
Dipropyl and diisopropyl acetals of p-chlorobenzaldehyde 4
were synthesized by refluxing a solution of the aldehyde
(4.21 g, 30 mmol), p-toluenesulfonic acid monohydrate
(200 mg), tripropyl orthoformate (8.56 g, 45 mmol) and
triisopropyl orthoformate (8.56 g, 45 mmol), respectively,
in the corresponding dry alcohol (6 mL) for 12 h in an argon
atmosphere. The reaction mixture was neutralized with an
aqueous solution of sodium carbonate, the aqueous layer
was extracted with diethyl ether (once 5 mL), and after
drying with sodium carbonate, the solvent was removed.
Vacuum destillation over a 10 cm Vigreux column afforded
at 131–133 8C (w10 mbar) pure p-chlorobenzaldehyde
dipropyl acetal (4.6 g, 19.0 mmol, 63%) and at 120–122 8C
(w10 mbar) p-chlorobenzaldehyde diisopropyl acetal
(4.8 g, 19.8 mmol, 66%), respectively.
All analytical reaction mixtures of the acetalizations were
prepared in clean (for cleaning glass flasks were stored for
8 h in a KOH/iso-propanol bath, washed intensively with
water, demineralized water, and acetone, successively),
oven-dried (5 h) and flame-dried 10 mL (for 2 mmol scale;
25 and 250 mL flasks for larger scale) one-necked glass
flasks were tightly sealed with a plastic plug. Two
millimoles of the respective carbonyl compound (for
catalyst loading of 0.1 and 0.01 mol% a 20 mmol scale
was used, for 0.001 mol% 200 mmol scale) and organo-
catalysts 1 (various loadings: 1.0 [10 mg/2 mmol], 0.1
[10 mg/20 mmol], 0.01 [1 mg/20 mmol], and 0.001 mol%
[1 mg/200 mmol scale] relative to the carbonyl compound)
were weighted out directly into the flasks and were
dissolved in 2 equiv of the corresponding alkyl orthofor-
mate and alcohol (methanol, ethanol, propanol, and
isopropanol, respectively) by intensive stirring (900 rpm)
with a new magnetic stirring bar wrapped with plastics
(size: 0.8 cm for 2 mmol, 1.4 cm for larger scale experi-
ment); stirring was continued until completion of the
reaction. The volume of the alcohol was adjusted relative
the volume of alkyl orthoformate, to keep total volume
constant (1.16 mL) making all experiments comparable to
each other (Table 2). For the formation of cyclic acetals
2 mmol of carbonyl compound, 4 equiv 1,2-ethandiol,
2 equiv triethyl orthoformate, and 0.25 mL THF as
cosolvent were mixed; all reactions were carried out at
room temperature (25 8C); the reaction time measurements
started with the addition of the alcohol, that served as
reagent as well as solvent; the volumes were measured with
1 and 2 mL pipettes. Every mixture containing catalyst was
prepared twice, and for detection of catalytic efficiency all
experiments were accompanied by a parallel control
experiment under same conditions, but without catalyst.
Samples (0.8–1.2 mL; volume depended on progress of
reaction) were taken directly from the stirred homogenous
reaction mixture by a Hamilton syringe (10 mL) and were
injected immediately to record the GC chromatogram. The
course of each acetalization was monitored by integrating
the educt/product ratio. Signals were assigned by injecting
4.5.1. p-Chlorobenzaldehyde dipropyl acetal. Colorless
liquid, IR (neat): nZ2964, 2937, 2877, 1490, 1339, 1205,
1090, 1067, 1042, 1016, 809; 1H NMR (400 MHz, CDCl3):
dZ0.95 (t, 3H, JZ7.5 Hz), 1.58–1.67 (m, 2H, JZ7.4 Hz),
3.38–3.36 (m, 2H), 5.5 (s, 1H), 7.27–7.34 (m, 2H), 7.37–
7.42 (m, 2H); 13C NMR (100 MHz, CDCl3): dZ10.7 (CH3),
22.9 (CH2), 66.9 (CH2), 100.7 (CH), 128.1 (CH), 128.2
(CH), 133.9 (Cq), 137.7 (Cq); HRMS calcd C13H19ClO2
242.1074; found: 242.1091; CHN-analysis: calcd C 64.32,
H 7.89; found C 64.54, H 8.16.
4.5.2. p-Chlorobenzaldehyde diisopropyl acetal. Color-
less liquid, IR (neat): nZ2973, 2931, 1599, 1491, 1466,
1381, 1324, 1295, 1204, 1180, 1126, 1089, 1075, 1035,
1
1015, 943, 833, 815 cmK1; H NMR (400 MHz, CDCl3):
1.13–1.19 (m, 6H), 3.85–3.94 (m, 1H, JZ6 Hz), 5.03 (s,
1H), 7.27–7.34 (m, 2H), 7.37–7.42 (m, 2H); 13C NMR
(100 MHz, CDCl3): dZ22.4 (CH3), 23.0 (CH3), 67.9 (CH),
98.5 (CH), 128.1 (CH), 128.2 (CH), 133.8 (Cq), 139.0 (Cq);
HRMS calcd C13H19ClO2 242.1074; found: 242.1086;
CHN-analysis: calcd C 64.32, H 7.89; found C 64.47, H
8.09.
4.6. Synthesis of 1,3-dioxolanes as reference compounds
In a oven-dried 50 mL one-necked flask equipped with a
water separator and a reflux condenser a mixture of 0.1 mol
of the corresponding freshly distilled carbonyl compound,
7.45 g (0.12 mol) 1,2-ethandiol, 30 mL toluene, and 150 mg
p-toluenesulfonic acid monohydrate were magnetically
stirred and refluxed until no more water separated. For
work-up the reaction mixture was poured into an aqueous
saturated solution of NaHCO3 (20 mL), the organic layer
Table 2. Volumes of orthoformates (2 equiv/4 mmol) and alcohols for
2 mmol scale experiments
Orthoformate
Volume (mL)
Alcohol
Volume (mL)
Trimethyl
Triethyl
Tri-n-propyl
Triisopropyl
0.44
0.66
0.87
0.87
Methanol
Ethanol
1-Propanol
2-Propanol
0.72
0.50
0.29
0.29