Lithium Hexamethyldisilazide → tert-Butyl 2-(4-((5R,7R)-2-oxo-3-oxa-1-azaspiro[4.4]nonan-7-yl)phenyl)acetate

HRID 2199470Notes

Reaction equation

HRID 2199470 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][C@@:10]3([NH:14][C:13](=[O:15])[O:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br-].[C:29]([O:33][C:34](=[O:37])[CH2:35][Zn+])([CH3:32])([CH3:31])[CH3:30]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2]>[O:15]=[C:13]1[O:12][CH2:11][C@:10]2([CH2:16][CH2:17][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([CH2:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:37])=[CH:3][CH:4]=3)[CH2:9]2)[NH:14]1

Participants

7

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 86730035(5R,7R)-7-(4-bromophenyl)-3-oxa-1-azaspiro[4.4]nonan-2-oneHCID 178451181HCID 178451181, compound

Product 1

HCID 86730040tert-Butyl 2-(4-((5R,7R)-2-oxo-3-oxa-1-azaspiro[4.4]nonan-7-yl)phenyl)acetate

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 129828017Ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+);(2,3,4,5-tetraphenylcyclopenta-1,4-dien-1-yl)benzeneCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of (5R,7R)-7-(4-bromophenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (Int. 4, 2.1 g, 7.09 mmol) in THF (25.3 ml) at room temperature was added LiHMDS (7.80 ml, 7.80 mmol). The solution was stirred for 15 min. Next, Pd2(dba)3 (0.195 g, 0.213 mmol), 1,2,3,4,5-pentaphenyl-1′-(di-t-butylphosphino)ferrocene (0.151 g, 0.213 mmol), and (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide, tetrahydrofuran (7.07 g, 21.27 mmol) were sequentially added. The slurry was stirred at 24° C. for 2 h. LCMS analysis showed complete consumption of the starting material. The reaction mixture was diluted with ethyl acetate and washed with 1M HCl. The organic layer was dried over MgSO4, filtered and concentrated. The crude material was purified on a silica gel cartridge (40 g) using hexane: acetone 100:0 to 0:100 over 25 CV. tert-Butyl 2-(4-((5R,7R)-2-oxo-3-oxa-1-azaspiro[4.4]nonan-7-yl)phenyl)acetate (2.35 g, 7.09 mmol) was isolated. HPLC retention time=0.95 min (Condition I): LC/MS M+1=332: 1H NMR (400 MHz, chloroform-d) δ 7.27-7.21 (m, 2H), 7.21-7.15 (m, 2H), 5.11 (br. s., 1H), 4.40-4.26 (m, 2H), 3.53 (s, 2H), 3.22-3.01 (m, 1H), 2.36 (dd, J=13.2, 7.3 Hz, 1H), 2.25-2.10 (m, 2H), 2.04-1.92 (m, 2H), 1.91-1.76 (m, 1H), 1.47 (s, 9H).

Workup

  1. stirringThe slurry was stirred at 24° C. for 2 h
  2. customconsumption of the starting material
  3. additionThe reaction mixture was diluted with ethyl acetate
  4. washwashed with 1M HCl
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude material was purified on a silica gel cartridge (40 g)

Sources & evidence

ORD record
ord-d44766dcf659430a819c48ec172e246f
Source dataset
uspto-grants-2016_06
Patent number
US09359286B2

Reaction notes

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