Organic Syntheses, CV 9, 230
Submitted by Angela Marinetti and Philippe Savignac
1.
Checked by Catherine Dubuisson and Louis S. Hegedus.
1. Procedure
A.
Diethyl (dichloromethyl)phosphonate,
1. An oven-dried,
1-L, four-necked, round-bottomed flask (or a
1-L, three-necked flask with a Claisen head fitted in a side neck) is fitted with an
efficient mechanical stirrer,
thermometer,
reflux condenser with a bubbler, and a
200-mL, pressure-equalizing addition funnel with a
nitrogen inlet. Under a gentle flow of
nitrogen the flask is charged with
400 mL of tetrahydrofuran (THF) (Note
1). The addition funnel is charged with a
1.9 M solution of isopropylmagnesium chloride in diethyl ether (83 mL, 0.158 mol) (Note
2). The mixture is cooled to −78°C with a dry ice/acetone bath (Note
3), and
isopropylmagnesium chloride is added over a few minutes with stirring. At this temperature, a solution of
diethyl (trichloromethyl)phosphonate (38.3 g, 0.150 mol) (Note 4) in tetrahydrofuran (50 mL) is added dropwise over 15 min. The resulting solution is stirred for an additional 15 min at −78°C producing a clear orange solution. Anhydrous
ethanol (12 g, 0.260 mol) in tetrahydrofuran (15 mL) is added dropwise at −78°C, producing a clear yellow solution. The resulting mixture is stirred for a few minutes, then allowed to warm slowly to −40°C. The reaction mixture is poured into a
beaker containing a stirred mixture of
3 M hydrochloric acid (70 mL), and an equal volume of crushed ice and
dichloromethane (70 mL). The yellow color initially dissipates, but the solution becomes yellow orange upon warming to room temperature. The organic layer is separated, and the aqueous layer is extracted with
dichloromethane (2 × 60 mL). The extracts are combined and dried over anhydrous
magnesium sulfate. After the filtration, the solvents are evaporated on a
rotary evaporator. The bright yellow, crude liquid (
36.3 g) is transferred to a
pear-shaped flask fitted with a
10-cm Vigreux column and distilled under reduced pressure to give
26.6 g (
80%) of
diethyl (dichloromethyl)phosphonate, 1, as a pale yellow liquid, bp
115–119°C/9 mm, >90% pure by
1H,
13C and
31P NMR spectroscopy (Note
5) and (Note
6).
B.
(4-Methoxyphenyl)ethyne,
2. An oven-dried, 1-L, four-necked, round-bottomed flask is fitted as above, flushed with
nitrogen, and charged with a solution of
butyllithium in hexane (1.56 M, 92 mL, 0.143 mol) (Note
7). The solution is cooled with stirring to −20°C with a dry ice/acetone bath and a solution of
diisopropylamine (15.1 g, 0.149 mol) (Note
8) in
tetrahydrofuran (220 mL) (Note
1), is added dropwise over 15 min. The resulting clear solution is cooled to −78°C and treated by the dropwise addition of a solution of
1 (30 g, 0.136 mol) and
4-methoxybenzaldehyde (18.1 g, 0.133 mol) (Note
8) in
tetrahydrofuran (60 mL) over 30 min. The resulting brown solution is stirred at −78°C for an additional 30 min, then allowed to warm slowly to 0°C over 60 min. The resulting mixture is then cooled to −78°C and a solution of
butyllithium (1.56 M in hexane, 183 mL, 0.285 mol) (Note
7) is added dropwise over 20 min. The resulting brown solution is stirred at −78°C for an additional 30 min, then allowed to warm slowly to 0°C over 60 min. At this temperature, the reaction mixture is quenched by the dropwise addition of
3 M hydrochloric acid to pH 5–6 (125–130 mL). The brown color has practically disappeared and the solution is yellow orange. The organic layer is separated and the aqueous layer is extracted with
diethyl ether (3 × 50-mL). The extracts are combined, washed with water (3 × 10 mL), and dried over anhydrous
magnesium sulfate.
Magnesium sulfate is removed by filtration and the solvents are evaporated on a rotary evaporator. The residue is dissolved in
hexane (200 mL) and filtered after 30 min. Solvent is again completely evaporated under reduced pressure. Crude product
2 thus obtained is purified by column chromatography on silica gel (Note
9) to afford
11.0 g (
63%) of pure
(4-methoxyphenyl)ethyne as a colorless liquid, bp
70–72°C (3 mm) that gives white crystals on standing in the freezer (Note
10).
2. Notes
1.
Tetrahydrofuran is obtained from S.D.S. Company and is purified by distillation from
sodium and benzophenone.
3. An alternative cooler was also used by the submitters consisting of a Dewar partially filled with liquid
nitrogen.
5. The crude liquid could be distilled using a Kugelrohr apparatus. The main fraction (
27.5 g,
83% yield) consists of a clear orange liquid that was collected at
145–155°C (oven temperature)/9–10 mm.
1H NMR (200 MHz, CDCl
3) indicates that this material is of the same purity as that from conventional distillation.
6. The product displays the following spectroscopic data:
31P NMR (81 MHz, CDCl
3) δ: +10.9;
1H NMR (200 MHz, CDCl
3) δ: 1.29 (t, 6 H, CH
3), 4.22 (dq, 4 H, CH
2), 5.6 (d, 1 H,
2J
H-P = 2, CH);
13C NMR (50 MHz, CDCl
3) δ: 16.2 (d, J
C-P = 5.9, CH
3), 60.7 (d, J
C-P = 178, CH), 65.0 (d, J
C-P = 7.4, CH
2) ppm.
9. The crude product is purified by chromatography (200 g of silica gel, Silitech 32–63 μm, purchased from ICN Biomedicals; column diameter, 5.5 cm). Elution is performed first with
hexanes (200 mL) and then with
hexanes-diethyl ether (20:1). Alternatively, the submitters purified the product by distillation from a pear-shaped flask using an
8-cm fractionating column.
10. The product displays the following spectroscopic data:
1H NMR (200 MHz, CDCl
3) δ: 3.02 (s, 1 H), 3.80 (s, 3 H), 6.8 (AA'BB', 2 H), 7.4 (AA'BB', 2 H);
13C NMR (50, MHz, CDCl
3) δ: 55.2 (OCH
3), 75.8 (CCH), 83.6 (CCH), 113.9 [CH (Ar)], 114.0 (C-C

CH), 133 [CH (Ar)], 159.9 (COCH-3) ppm.
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
The procedure described in Part A represents a convenient synthesis of
diethyl (dichloromethyl)phosphonate,
1, for large-scale preparations (up to 1 mol). The use of
isopropylmagnesium chloride instead of
butyllithium3,4 reduces the amount of by-products,
5 simplifies the purification step, and improves the yield. An alternative synthetic method for
1 is chlorination of
diethyl (chloromethyl)phosphonate;
6,7 however, yields and selectivities are lower than in the procedure described here.
Diethyl (dichloromethyl)phosphonate,
1, or the corresponding lithiated derivative, are useful intermediates in organic synthesis: 1,1-dichloroalkenes
3,4,6 as well as terminal alkynes
4 have been prepared.
Part B shows the use of
1 as starting material for the synthesis of
(4-methoxyphenyl)ethyne. The generation of the phosphorylated carbanion is performed through metalation with
lithium diisopropylamide (LDA). A mixture containing the phosphorus reagent
1 and the aldehyde is added directly to LDA, in order to trap the unstable phosphorylated, lithiated carbanion, thus preventing decomposition and side reactions. The formation of
(4-methoxyphenyl)ethyne described here is an example of a general synthetic method for the conversion of aldehydes into acetylenes, on a large scale, by means of
diethyl (dichloromethyl)phosphonate,
1. The methodology is well suited for the synthesis of a wide variety of acetylenic compounds, such as C
9H
19C

CH, (C
2H
5)
2CHC

CH, C
6H
5CH=CHC

CH,
4 and analogous terminal alkynes. Several methods for the preparation of alkynes based on phosphorus reagents have been reported previously. Each of these procedures can be regarded as an extension of the Wittig-Horner olefin synthesis. In the final step the olefins are converted into the corresponding alkynes. The first method that employed the PPh
3-CBr
4 couple (or PPh
3- CBr
4-
zinc dust) was introduced by Corey and Fuchs
8 (1972). The amounts of PPh
3 involved (2 or 4 equiv and of PPh
3O formed during the reaction, are obstacles for large scale synthesis.
Dimethyl diazomethylphosphonate first prepared by Seyferth
9 in 1971 was shown, by Colvin and Hamill
10 in 1977, then by Gilbert and Weerasooriya
11 in 1982, to be an effective reagent for the transformation of aldehydes, alkyl aryl ketones or diaryl ketones into alkynes. However, this reagent is rather difficult to prepare (four steps, 46% yield), and very hazardous to handle (explosive decomposition on distillation), and therefore is unsuitable for preparative scale synthesis.
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