The preparation of 3-substituted-1,5-dibromopentanes as precursors to heteracyclohexanes

The methodology to prepare 3-substituted 1,5-dibromopentanes I and their immediate precursors, which include 3-substituted 1,5-pentanediols VII or 4-substituted tetrahydropyrans VIII, is surveyed. Such dibromides I are important intermediates in the preparation of liquid crystalline derivatives containing 6-membered heterocyclic rings. Four dibromides 1a–1d containing simple alkyl and more complex fragments at the 3-position were prepared. 3-Propyl- and 3-pentyl-pentane-1,5-diol (2a,b) were prepared starting from either glutaconate or malonate diesters, while tetrahydropyrans 3c and 3d were obtained from tetrahydro-4H-pyran-4-one. The advantages and disadvantages of each route are discussed. Dibromides 1c and 1d were used to prepare sulfonium zwitterions 11c and 11d.

A solution of diethyl 3-propylglutarate (4, 4.9 g, 21.3 mmol) in anhydrous THF (50 mL) was added dropwise to a suspension of LiAlH 4 (1.62 g, 42.6 mmol) in anhydrous THF (150 mL) at 0 °C in a 500 mL 3 necked flask under an Ar atmosphere. The reaction was warmed to rt and gently heated under reflux overnight. The reaction was cooled to 0 °C, carefully quenched with H 2 O (10 mL) and then 2 M KOH (25 mL). After 30 minutes, the white precipitate was removed by filtration and washed with Et 2 O (100 mL). The filtrate was dried (MgSO 4 ), filtered and evaporated to give 3.10 g (99% yield) of 3-propyl-1,5pentanediol (2a) as a colorless oil which was used without further purification: 1   Procedure A. A suspension of anhydrous THF (15 mL), olefin 6 (25 mmol), 10% Pd/C (10 wt %) was hydrogenated by the balloon method (760 mmHg). The reaction progress was monitored by 1 H NMR until starting material was no longer observed. The suspension was filtered through Celite and evaporated. The pyran was further purified by passage through a short plug of silica gel (eluent: CH 2 Cl 2 /hexane, 1:9) and by bulb-tobulb distillation.

Preparation of 4-(4-propylphenethyl)tetrahydro-2H-pyran (3d).
Following a modified literature procedure for the coupling of aryl chlorides to alkylzinc reagents [6], a solution of 4-(4-chlorophenethyl)tetrahydro-2H-pyran (3e, 3.17 g, 14.1 mmol) in anhydrous THF (5 mL) was added to a homogeneous solution of propylmagnesium chloride (21 mL, 42 mmol, 2 M in Et 2 O), anhydrous ZnCl 2 (6.75 g, 49.5 mmol), anhydrous LiCl (3.59 g, 85 mmol), and PEPPSI-IR (0.202 g, 0.3 mmol, 2 mol %) in a 2:1 mixture of anhydrous NMP/THF (150 mL). The reaction became exothermic, the solution became dark brown and was left to stir overnight at rt. Reaction progress was monitored by 1 H NMR and additional catalyst or organozinc reagent was S8 added if necessary. The reaction was quenched with CH 3 OH, the reaction mixture filtered, and excess solvent removed in vacuo. 10% HCl (100 mL) was added to the dark brown viscous oil, and the suspension extracted with hexanes (4  30 mL). The organic layers were combined, dried (MgSO 4 ) and evaporated to give 3.81 g of a yellow oil. The yellow oil was passed through a short plug of silica gel (eluent: CH 2 Cl 2 /hexane, 1:9) to afford 2.45 g of a colorless oil which was further purified by bulb-to-bulb distillation to EtOH for MeOH, diethyl 3-propylglutarate 4 was obtained in 49% yield (33.5 g).

Preparation of dimethyl 3-pentylglutarate (5).
A mixture of dimethyl malonate (85. mmol) under an Ar atmosphere. The deep red solution of phosphorane was maintained at S11 0 °C for 1 h, and a solution of tetrahydropyran-4-one (50 mmol, 0.7 equiv) in anhydrous CH 2 Cl 2 (20 mL) added dropwise. The reaction mixture was stirred overnight at rt and diluted with sat. NH 4 Cl (100 mL) to yield a red biphasic solution. The excess organic solvents were removed in vacuo, and the aqueous layer treated with hexane (200 mL) to yield an orange precipitate. The mixture was filtered and washed with additional hexane.
The hexane layer was separated, and the aqueous layer further extracted with hexane (3  50 mL). The combined organic layers were dried (MgSO 4 ), filtered and evaporated. The product was passed through a short plug of silica gel (eluent: CH 2 Cl 2 /hexane, 1:9) and further purified by bulb-to-bulb distillation to giving the pure olefin.

Preparation of 4-Chlorophenethyl Bromide (8)
In a 1 L, 3-necked flask, a solution of methanol (300 mL), H 2 SO 4 (30 mL), and 4chlorophenylacetic acid (30 g, 176 mmol) was heated under reflux for 12 h. The reaction was cooled to rt, and excess CH 3 OH removed in vacuo. H 2 O (300 mL) was added, and the reaction mixture extracted with Et 2 O (4  75 mL). The organic layers were combined, washed with sat. NaHCO 3 solution (3  100 mL), dried (MgSO 4 ), filtered and evaporated S16 to afford 32.1 g (99% yield) of methyl 4-chlorophenylacetate as a slight yellow oil which was used with further purification: 1  In a 1 L, 3-necked flask, a solution of 4-chlorophenethyl alcohol (23.0 g, 147 mmol) in anhydrous toluene (100 mL) under an Ar atmosphere was carefully treated dropwise with PBr 3 (6 mL, 64 mmol) at 0 °C. The solution was warmed to rt and heated under reflux for 3 h. The resulting orange suspension was re-cooled to 0 °C and treated with a 1:1 NaHCO 3 /Na 2 S 2 O 3 solution (by mass, 100 mL). The biphasic system was filtered to remove insoluble material, and the aqueous layer removed. The organic layer was further washed with the 1:1 solution of NaHCO 3 /Na 2 S 2 O 3 (2  100 mL), dried (MgSO 4 ), filtered and evaporated. The resulting light yellow oil was passed through a short plug of silica gel (eluent: hexanes) and further purified by bulb-to-bulb distillation (60 °C, 0.3 mmHg)