Methyl iodide → tert-Butyl 7-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate

HRID 749909Notes

Reaction equation

HRID 749909 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:20]C(N1CCC2(OCCO2)CC1)=O)(C)(C)[CH3:17].[Li]C(CC)C.CI>CN(CCN(C)C)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([O:20][CH2:16][CH2:17][O:14]2)[CH2:10][CH:9]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 6328Methyl iodideHCID 12992764tert-Butyl 2-methyl-4-oxopiperidine-1-carboxylateHCID 14271588tert-Butyl 1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylateHCID 178418400CID 53628100

Product 1

HCID 14271604tert-Butyl 7-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8037N,N,N',N'-TetramethylethylenediamineSolvent

Procedure

2-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester. A solution of 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (2.97 g) in TMEDA (2.2 mL) was cooled to −78° C. and sec-BuLi (1.8 M in THF, 13 mL) was added dropwise. The resulting yellow solution was aged at −78° C. for 1 h. Methyl iodide (1.5 mL) was added and the mixture was warmed from −78° C. to RT over 16 h. The reaction mixture was poured into water (800 mL) and extracted with EtOAc. The combined organic extracts were washed with H2O, brine, and dried over Na2SO4. Purification on SiO2 (330 g, 5 to 20% EtOAc/hexanes) provided 1.65 g of 7-methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester. Multiple aliquots of this ester were combined (2.29 g), treated with 5 mL of conc. HCl in 10 mL of dioxane, and heated at 65° C. for 6 h. The solvent was removed and the residue was dissolved in CH2Cl2 and treated with di-tert-butyldicarbonate (1.0 g). After 5 d, the mixture was diluted with satd. aq. NaHCO3 and H2O, and extracted with CH2Cl2. Purification on SiO2 (120 g, 5 to 15% EtOAc/hexanes) provided 1.40 g of the desired product as a white solid. 1H NMR (500 MHz, CDCl3): 4.69-4.59 (m, 1H), 4.21-4.12 (m, 1H), 3.30-3.20 (m, 1H), 2.66-2.57 (m, 1H), 2.47-2.36 (m, 1H), 2.32-2.23 (m, 1H), 2.22-2.15 (m, 1H), 1.42 (s, 9H), 1.11 (d, J=7.1 Hz, 3H).

Workup

  1. temperaturethe mixture was warmed from −78° C. to RT over 16 h
  2. extractionextracted with EtOAc
  3. washThe combined organic extracts were washed with H2O, brine
  4. dry with materialdried over Na2SO4
  5. customPurification on SiO2 (330 g, 5 to 20% EtOAc/hexanes)

Sources & evidence

ORD record
ord-a3ee9ca201eb4c759464d6716d093540
Source dataset
uspto-grants-2008_07
Patent number
US07402680B2

Reaction notes

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