Reaction #58684

Reaction equation

Intermediate 53

piperidine-1,3-dicarboxylic acid 1-tert-butyl ester-3-methyl ester

NaHMDS

iodomethane

→

3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester

Yield 95.8%

Solvents

THF

Conditions

Workup

1. 1
   TemperatureThe reaction was cooled
2. 2
   Otherquenched with saturated NH4Cl
3. 3
   OtherThe layers were separated
4. 4
   Extractionthe aqueous layer was extracted three times with 20 ml of EtOAc
5. 5
   DryingThe organic phase was dried over Na2SO4
6. 6
   Filtrationfiltered
7. 7
   Concentrationconcentrated under reduced pressure
8. 8
   OtherThe oil was purified by silica chromatography

Procedure

To a −78° C. stirred solution of Intermediate 53 (2.22 g, 9.13 mmol) in dry THF (30 ml) was added NaHMDS (sodium hexamethyldisilazane) (1.0 M in THF, 10.03 mmol) dropwise. The reaction was stirred at this temperature for 30 minutes and then iodomethane (0.682 ml, 10.95 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight with good stirring. The reaction was cooled and then quenched with saturated NH4Cl. The layers were separated and the aqueous layer was extracted three times with 20 ml of EtOAc and the organic extracts were combined. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The oil was purified by silica chromatography using hexanes/EtOAc (0>15%) to yield 2.25 g (95.8%) of 3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (Intermediate 54). 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (s, 3 H), 1.3 (s, 9 H), 1.4 (m, 2 H), 1.9 (m, 2 H), 3.0 (d, J=13.2 Hz, 1 H), 3.1 (m, 1 H), 3.3 (m, 1 H), 3.5 (s, 3 H), 3.7 (d, J=13.4 Hz, 1 H).

Source