SYNTHESIS OF (R)- and (S)-2-METHYLOCTANAL

(S)-Phenylalanine ethyl ester hydrochloride.¹²⁴ 

• To a stirred, ice-cold suspension of (S) -phenylalanine (30 g, O.182mol) in absolute ethanol (800 ml), thionyl chloride (32.5 g, 0.273 mol) is added dropwise, and the reaction mixture is then heated under reflux for 3.5 hours. 

• The pale yellow solution is allowed to stand at room temperature overnight, and then the ethanol is evaporated in vacuo to leave colourless crystals of the hydrochloride which are stirred with dry ether, filtered off and dried in vacuo.

(S)-2-Amino-3-phenylpropan-l-ol[(S)-phenylalaninol].¹²⁴ 

• To a solution of  sodium borohydride (3.5 g, 0.092 mol) in 50 per cent aqueous ethanol (50 ml) is added dropwise a solution of (S)-phenylalanine ethyl ester hydrochloride (5.0 g, 0.022 mol) in 50 per cent aqueous ethanol (50 ml). 

• After the resulting mixture is refluxed for 4.5 hours, ethanol is evaporated in vacuo. 

• The aqueous solution thus obtained is then extracted with ethyl acetate and the extract washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. 

• Evaporation of the ethyl acetate under reduced pressure affords (S)-phenylalaninol (2.8 g, 84%) as a pale yellow solid m.p. 85-92 °C. 

• Recrystallisation from ether gives colourless crystals of m.p. 91-93 °C, [𝛂]ᴅ²⁵ - 25.6° (c. 1.037 in EtOH).

(S)-(— )-2-Amino-l-methoxy-3-phenylpropane. 

• A solution of (S)-phenyl-alaninol (18.4g, 0.122mol) in 250 ml of anhydrous tetrahydrofuran is added dropwise to a stirred suspension of potassium hydride (5.23 g, 0.130mol, pentane washed) in 100 ml of tetrahydrofuran at 25 °C under nitrogen. 

• The resulting pale yellow gelatinous mixture is allowed to stand overnight and then a solution of methyl iodide (17.0g, 0.119mol) in 150 ml of tetrahydrofuran is added dropwise over 2 hours. 

• Mixing is accomplished by external shaking since the gelatinous mixture would not stir with a magnetic stirrer bar. 

• The reaction components are then allowed to mix for an additional 3 hours and then poured into 1 litre of cold saturated brine, extracted thrice with ether, dried over anhydrous sodium sulphate, and concentrated to give 24.9 g of crude product. 

• Distillation gives 17.1 g, b.p. 55-59 °C/ 0.1 mmHg, of a clear oil which on standing becomes cloudly and rapidly produces a white precipitate which is found to be the carbonate. 

• Since this experiment was performed it has been found that conversion of the freshly distilled methoxyamine to its hydrochloride salt is a more convenient way to store the compound. 

• Thus the methoxyamine (17.0g) immediately after distillation is dissolved in 700 ml of absolute ethanol and dry hydrogen chloride bubbled in for 10 minutes. 

• The resulting solution is concentrated in vacuo to furnish 20.5 g of a colourless solid which is recrystallised from ethanol-ether (13:1), m.p. 151-152 °C, [a]i? 8 + 19.7° (a 2.5 in EtOH), 5 (D 2 0) 2.90 (d, 2H), 3.34 (s, 3H), 3.54 (s, 2H), 3.59 (m, 1H), and 7.37 (broad s, 5H). 

• To release the free methoxyamine, it is dissolved in 5 per cent potassium carbonate solution and extracted with ether, dried over anhydrous sodium sulphate and concentrated. 

• Bulb-to-bulb distillation at 52°C/0.1mmHg gives a clear oil, [oe]^ -14.7° (c. 6 in C 6 H 6 ); p.m.r. (CDC1 3 ) 51.75 (broad s, 2H, disappears on D 2 shake) 2.68 (m, 2H), 3.35 (broads, 6H) and 7.24 (s, 5H).

Formation of aldimines from propanal and octanal

• To a stirred solution (0°C) of lOmmol of the methoxyamine dissolved in 30 ml of benzene (CAUTION) (previously washed with concentrated sulphuric acid and distilled) is added lOmmol of the pure aldehyde. 

• An immediate cloudiness usually results. 

• The mixture is allowed to warm to room temperature and c. 15 g of anhydrous sodium sulphate added. 

• After stirring an additional 30-40 minutes, it is filtered and the sodium sulphate washed thoroughly with dry ether. 

• The solvent is removed first with aspirator pressure and then with a vacuum pump (0.5 mm) to generally furnish 9.5-10 mmol of the aldimine as a colourless oil. 

• The aldimines are dissolved in tetrahydrofuran (0.4 m) and stored at —20 to — 30 °C. 

• Attempts to store the aldimines as neat liquids result in deterioration. 

• The solutions of aldimines are conveniently transferred via a syringe to reaction vessels.

(R)- and (S)-2-MethyIoctanaI

• The flask is charged with 10 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere.

•  Freshly distilled di-isopropylamine (1.54 ml, 11 mmol) is added via a syringe and the solution cooled to °C. Butyllithium (4.6 ml of a 2.4 m solution in hexane) is added and the solution stirred at °C for 40 minutes and then cooled to — 23 °C (dry ice-carbon tetrachloride). 

• The aldimine (lOmmol) in 25ml of tetra-hydrofuran is added via a syringe over 5 minutes. 

• The resulting solution (generally yellow) is stirred at — 23 °C for 30 minutes and then cooled to — 78 °C (dry ice-propanol). 

• The alkyl halide (hexyl or methyl iodide) (10 mmol) dissolved in 5 ml of tetrahydrofuran is then added and the reaction mixture stirred for 2-7 hours at —78 °C (1). 

• After warming to room temperature and addition of 50 ml of ether, the cloudy mixture is poured into 100 ml of water and the phases separated. 

• The aqueous phase is extracted with ether and the combined organic phases are washed with brine, dried over anhydrous sodium sulphate and concentrated. 

• The crude alkylated aldimines are hydrolysed by dissolving in 30 ml of pentane and shaking for 5 minutes in a separating funnel with an aqueous acetic acid-sodium acetate solution (prepared from 37.5 ml of acetic acid, 37.5 ml of water and 16.2g of sodium acetate). 

• The layers are separated and the aqueous layer extracted once with 30 ml of pentane. 

• Both layers are kept (2). The combined pentane layers are washed successively with water, 10 per cent sodium hydrogen carbonate, water and then dried. 

• Evaporation of the filtered pentane solution gives the crude aldehyde as a pale yellow oil. 

• Bulb-to-bulb distillation at 90 °C/ 4mmHg furnishes a clear colourless product which by g.l.c. analysis is shown to be 70-75 per cent pure 2-methyloctanal. 

• The contaminant in the case of the reaction between the aldimine of propanal and hexyl iodide, is hexyl iodide, and in the case of the reaction between the aldimine of octanal and methyl iodide, is octanal. 

• These impurities arise from an incomplete metallation reaction which leads in the first instance to generation of propanal and hexyl iodide in the work-up procedure, and in the second instance to the generation of octanal and methyl iodide. 

• In the final bulb-to-bulb distillation the more volatile propanal or methyl iodide is removed from the respective 2-methyl-octanal distillates, leaving the contaminants noted above (3).

Notes to keep in mind:

1. The reaction is monitored by withdrawing a 0.5 ml aliquot, quenching with water, and n.m.r. analysis of the extracted organic residue.

2. The chiral methoxyamine is recovered from the aqueous solution by neutralisation with solid potassium hydroxide and extraction with ether. The ethereal extract is washed with brine, dried over potassium carbonate and concentrated to give the crude chiral amine in 80-88 per cent yield. Distillation affords the pure amine (70- 75% recovery) with [a] values which indicate that no racemisation has occurred.

3. The literature authors prepared mixtures of enantiomerically pure 2-methyl-octanal ( [𝛂]ᴅ²⁵ -8.90 °C) (isolated by preparative g.l.c. from the sample prepared by the above procedure from the aldimine of propanal and hexyl iodide) containing w/w amounts of 12.7, 25.7 and 44.6 per cent of hexyl iodide. The [𝜶] D values of these mixtures were plotted against the weight per cent to give a linear relationship. The g.l.c. composition of the reaction product and its extrapolated specific rotation thus allowed an ee per cent value to be calculated. In a similar way the ee per cent of the

reaction of the aldimine of octanal and methyl iodide was calculated from the mixtures of octanal with the optically pure 2-methyloctanal of 55.4, 74.3 and 87.3 per cent and the plot weight per cent v. [𝜶] D was again linear.