Checked by Ronaldo A. Pilli, Kenneth S. Kirshenbaum, Clayton H. Heathcock, and K. Barry Sharpless.
1. Procedure
A.
Diethyl hydroxymethylphosphonate. To a
250-mL, round-bottomed flask equipped with a
magnetic stirring bar and an
efficient reflux condenser are added
69 g (64.4 mL, 0.5 mol) of diethyl phosphite (Note
1),
15 g (0.5 mol) of paraformaldehyde, and
5.1 g (0.05 mol) of triethylamine. The mixture is placed in an
oil bath preheated to 100–120°C. The temperature is increased to 120–130°C, and the mixture is stirred at this temperature for 4 hr. The stirring bar is removed, the flask is transferred to a
rotary evaporator, and most of the
triethylamine is removed by heating under reduced pressure of ca. 15 mm and with a bath temperature of ca. 80°C. Kugelrohr distillation at 125°C (0.05 mm) (Note
2) gives
41.4–54.9 g (
49–65%) of material of sufficient purity for the next step (Note
3) and (Note
4).
B.
Diethyl [(2-tetrahydropyranyloxy)methyl]phosphonate. A mixture of
33.63 g (0.2 mol) of diethyl hydroxymethylphosphonate,
21 g (0.25 mol) of dihydropyran, and
150 mL of diethyl ether is placed in a
stoppered flask, and 20 drops of
phosphorus oxychloride is added while the contents are swirled manually. After 3 hr at room temperature the reaction is monitored by TLC (Note
5). The mixture is diluted with
diethyl ether, transferred into a
separatory funnel, and shaken successively with
100 mL of saturated sodium bicarbonate solution, 100 mL of water, and
100 mL of saturated sodium chloride solution. The
ether solution is dried over
MgSO4, filtered, and the
ether is removed with a rotary evaporator. Kugelrohr distillation of the residue (110°C, 0.05 mm) gives
42.4–46.9 g (
84–93%) of material of sufficient purity for use in homologation reactions (Note
6) and (Note
7).
2. Notes
2. Attempted isolation of
diethyl hydroxymethylphosphonate by standard vacuum-distillation technique is accompanied by extensive decomposition. The use of Kugelrohr apparatus allows the isolation to be accomplished at a lower temperature, and therefore the product is obtained in higher yield. Alternatively, the checkers found that distillation using a 2-in. wiped-film molecular still. (Pope Scientific, Inc.) significantly raised product yields, especially when the reaction was performed on a larger scale (Note
3) and (Note
6).
3. The checkers found that reactions run on up to four times the present scale and rectified using a molecular still (wall temperature 110–120°C, 0.10 mm) gave yields of
89–94%.
Warning: On this larger scale (i.e., four times the present scale) a brief runaway was experienced and some material that escaped from the condenser was caught in a trap; however, the yield was still excellent (94%).
4. On TLC [silica, visualization with 1.5%
phosphomolybdic acid spray and heating] the product has a retardation factor of ca. 0.1 with ethyl acetate development and ca. 0.3 with methanol–dichloromethane [5:95] development. The
1H NMR spectrum (CDCl
3) is as follows δ: 1.31 (t, 6 H,
J = 6.8), 3.87 (d, 2 H,
J = 7), 4.13 (m, 4 H), 5.34 (br s, 1 H, OH).
6. The checkers found that reactions run on up to nine times the present scale could be effected with only a small reduction in yield. Molecular still distillation (wall temperature 105–115°C, 0.10 mm) gave yields of
81–83%.
7. GLC analysis (0.5 × 200 cm 3% OV-17, 170°C,
helium flow = 30 mL/min) shows the product with a retention time of 5 min and a purity greater than
97% The
1H NMR spectrum (CDCl
3) is as follows δ: 1.35 (t, 6 H,
J = 7), 1.4–1.9 (m, 6 H), 3.4–4.45 (m, 8 H), 4.7 (m, 1 H).
3. Discussion
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