SYNTHESIS OF 7-ACETOXYHEPTANAL

STEP 1:           1-Acetoxy-4-iodobutane

• A 500-ml flask is fitted with an addition funnel, condenser and magnetic stirrer. Tetrahydrofuran (50 ml, 0.61 mol), acetic anhydride (100 ml, 1.0 mol), zinc dust (0.1 g, 1.5 mmol) are placed in it. Aqueous hydriodic acid (55%, 40 ml, 0.29 mol) is added dropwise at a rate that keeps the exothermic reaction at reflux.
• After the addition is complete, the mixture is allowed to cool for 1 hour and then poured into 200 ml of saturated aqueous sodium carbonate.
• The mixture is extracted with dichloromethane, dried with magnesium sulphate and the solvent evaporated.
• The residual oil is distilled to give the product, yield 56.7 g (80%), b.p. 76-78 °C/0.5 mmHg; p.m.r. (CDC1₃, TMS) 6 1.88 (m, 4H), 2.02 (s, 3H), 3.20 (t, 2H, J = 6 Hz, —CH₂I) 4.05 (t, 2H, J = 6 Hz, —CH₂.0Ac).

STEP 2:           2-(6-Acetoxyhexyl)-1,3-dioxane

• Copper(i) iodide (0.60 g, 3.1 mmol) and 1- acetoxy-4-iodobutane (12.1 g, 50.0 mmol) are cooled in a dry ice/propan-2-ol bath under a nitrogen atmosphere (1). 
• The Grignard reagent (2), prepared from 2-(2-bromoethyl)-1,3-dioxane' (12.19 g, 62.5 mmol) in 50 ml of tetra­hydrofuran, is added dropwise to the cooled solution. 
• This is stirred at —80 °C for 30 minutes, slowly raised to reflux temperature over a 2-hour period, and then heated at reflux for 6 hours. 
• The tetrahydrofuran is removed by rotary evaporation and the residue poured into aqueous ammonia/ ammonium chloride solution (800 ml). 
• The product is extracted with ether (3 x 50 ml), dried with magnesium sulphate and distilled.
•  A small amount of 1-acetoxy-4-iodobutane is recovered, and then the product is obtained in a yield of 8.86 g (77%), b.p. 90-100 °C/0.3 mmHg.

STEP 3:           7-Acetoxyheptanal 

• 2-(6-Acetoxyhexyl)-1,3-dioxane (4.60 g, 20.0 mmol), methanol (150 ml), glacial acetic acid (35 ml) and concentrated hydrochloric acid (1 ml) are stirred and left to stand for 3 days. 
• This mixture is poured cautiously into saturated sodium hydrogen carbonate solution (500 ml) and the product extracted with ether (3 x 200 ml). 
• The extract is dried with mag­nesium sulphate and evaporated to give the crude dimethyl acetal, which is then dissolved in glacial acetic acid (100 ml), water (10 ml) and hydrochloric acid (1 ml) and left to stand for 3 days. 
• The solution is poured cautiously into saturated aqueous sodium hydrogen carbonate (1 litre), made basic with additional sodium hydrogen carbonate, and the product extracted with ether (3 x 50 ml). 
• The extract is dried with magnesium sulphate, evaporated and the residue distilled to give the product, yield 3.10 g (90%), b.p. 93-98 °C/ 0.7 mmHg.

Notes to keep in mind:

1. The editors suggest that the apparatus consists of a 100-m1 two-necked flask fitted with a silicone rubber septum into which is inserted a syringe needle connected to a nitrogen feed and through which the reagents may be syringe-injected; the second arm of the flask is fitted with a reflux condenser the outlet of which is connected to a mercury bubbler.

2. The Grignard reagent is prepared by the following procedure ^{1 6}' with suitable adjustment of the quantities of reagents employed. A 50-m1 flask is equipped with a reflux condenser, a nitrogen atmosphere and magnetic stirring. In it are placed magne­sium turnings (0.97 g, 40 mmol), dry tetrahydrofuran (25 ml) and 2-(2-bromoethyl)- 1,3-dioxane^{l 6b} (5.85, 30 mmol) (or from Aldrich). This is heated to reflux and the heat immediately removed.The exothermic reaction is moderated at reflux by the occa­sional application of an ice bath. After 10 minutes, heat is applied to maintain reflux­ing for an additional 10 minutes. After cooling to room temperature the solution is drawn up into a 50-m1 syringe leaving excess magnesium behind.