Reaction #2067

Reaction equation

NaCNBH3

tetraethyl 3-oxopentane-1,1-bisphosphonate

bromothymol blue

benzylamine

NaCNBH3

→

tetraethyl 3-benzylaminopentane-1,1-bisphosphonate

Solvents

Acetic acid

methanol

Conditions

Workup

1. 1
   workup.ADDITIONwas added
2. 2
   workup.ADDITIONwas added
3. 3
   Otherthe reaction was quenched
4. 4
   workup.ADDITIONby adding concentrated HCl until the pH was less than 1
5. 5
   Otherthe solvents were removed in vacuo
6. 6
   Washwashed with diethyl ether (2×20 ml)
7. 7
   workup.ADDITIONby the addition of solid KOH
8. 8
   Extractionsaturated with NaCl, and extracted with dichloromethane (5×25 ml)
9. 9
   DryingThe combined extracts were dried (Na2SO4)
10. 10
    Concentrationconcentrated

Procedure

To a stirred solution of tetraethyl 3-oxopentane-1,1-bisphosphonate (0.50 g, 1.4 mmol) in methanol (5 ml) was added a small amount of bromothymol blue and benzylamine (0.75 g, 7.0 mmol). Acetic acid was added dropwise until the solution turned yellow (pH=6), and NaCNBH3 (57 mg, 0.9 mmol) was added. The resulting yellow solution was stirred at room temperature for 2 days, at which time more NaCNBH3 (20 mg) was added. After stirring a total of 4 days, the reaction was quenched by adding concentrated HCl until the pH was less than 1, and the solvents were removed in vacuo. The residue was taken up in water (10 ml) and washed with diethyl ether (2×20 ml). The aqueous layer was made basic (pH greater than 10) by the addition of solid KOH, saturated with NaCl, and extracted with dichloromethane (5×25 ml). The combined extracts were dried (Na2SO4) and concentrated to give tetraethyl 3-benzylaminopentane-1,1-bisphosphonate. This material was hydrolyzed by heating at reflux in concentrated HCl (6 ml) for 20 hours. The volatiles were removed under vacuum, the residue dissolved in water (10 ml) and concentrated under vacuum to give 0.49 g of Compound No. 159 as a hygroscopic foam.

Source