Reaction #65657

Reaction equation

t-butyl chloromethylsulfide

n-butyllithium

2-carbomethoxy-indan

sodium hydrogen carbonate

diisopropylamine

→

2-carbomethoxy-2-(t-butyl)thiomethylindan

Yield 61.0%

Solvents

—

hexanes

tetrahydrofuran

tetrahydrofuran

Conditions

Workup

1. 1
   workup.ADDITIONAdd, by dropwise addition
2. 2
   workup.STIRRINGStir at -70° C. for an additional 30 minutes
3. 3
   workup.DISTILLATIONadd trimethylsilyl chloride (freshly distilled from barium oxide, 1.0 mL, 7.8 mmol)
4. 4
   TemperatureAllow to warm to 10° C.
5. 5
   Otherevaporate the solvent in vacuo
6. 6
   Otherdry the residue under vacuum for 30 minutes
7. 7
   workup.STIRRINGStir for 15 minutes at room temperature
8. 8
   OtherSeparate the organic phase
9. 9
   Extractionextract the aqueous phase with methylene chloride (30 mL)
10. 10
    DryingCombine the organic phases, dry (MgSO4)
11. 11
    Otherevaporate the solvent in vacuo
12. 12
    Otherto give crude product as a brown oil (2.12 g, 98%)
13. 13
    OtherPurify by silica gel chromatography (30-70° C. methylene chloride/hexane)
14. 14
    Otherrecrystallize (methanol)

Procedure

Dissolve 2-carboxy-indan (2.5 g, 15.4 mmol) in methanol and cool to 0° C. Saturate with hydrochloride gas then add 2,2-dimethoxypropane (2-3 mL). Stir overnight then evaporate the solvent in vacuo. Purify by silica gel chromatography (2:1 methylene chloride/hexane) to give 2-carbomethoxy-indan as a water white oil. (2.04 g, 75%). Dissolve diisopropylamine (1.90 mL, 7.8 mmol) in anhydrous tetrahydrofuran (8 mL), cool to -20° C. and place under an argon atmosphere. Add, by dropwise addition, n-butyllithium (3.12 mL of a 2.5N solution in hexanes, 7.8 mmol) and stir for 20 minutes while cooling to -70° C. Add, by dropwise addition, a solution of 2-carbomethoxy-indan (1.34 g, 7.8 mmol) in anhydrous tetrahydrofuran (8 mL). Stir at -70° C. for an additional 30 minutes then add trimethylsilyl chloride (freshly distilled from barium oxide, 1.0 mL, 7.8 mmol). Allow to warm to 10° C., evaporate the solvent in vacuo and dry the residue under vacuum for 30 minutes. Suspend the residue in methylene chloride (30 mL), add zinc bromide (300 mg, 1.3 mmol) followed by t-butyl chloromethylsulfide (1.08 g, 7.8 mmol). Stir for 15 minutes at room temperature and add additional zinc bromide (500 mg, 2.2 mmol). Pour onto excess saturated sodium hydrogen carbonate and shake vigorously. Separate the organic phase and extract the aqueous phase with methylene chloride (30 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo to give crude product as a brown oil (2.12 g, 98%). Purify by silica gel chromatography (30-70° C. methylene chloride/hexane) and recrystallize (methanol) to give 2-carbomethoxy-2-(t-butyl)thiomethylindan as a crystalline solid (1.3 g, 61%).

Source