Dimethylacetamide → 5-(Benzyloxyacetamido)-6-cyanoindan-1-one

HRID 2407058Notes

Reaction equation

HRID 2407058 reaction equation
[CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1Br)[C:18](=[O:23])[CH2:17][CH2:16]2)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:25]([N:27](C)C)=O>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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:25]#[N:27])[C:18](=[O:23])[CH2:17][CH2:16]2)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 2

HCID 31374DimethylacetamideHCID 56655401HCID 56655401, compound

Product 1

HCID 566547195-(Benzyloxyacetamido)-6-cyanoindan-1-oneYield 85%

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
85 °C

Procedure

A 12 L, 4 neck flask was equipped with an overhead stirrer, an N2 inlet, a type-J Teflon® covered thermocouple, solid addition funnel, and a reflux condenser. The flask was charged with 2-benzyloxy-N-(6-bromo-I-oxoindan-5-yl)acetamide (2000 g, 5.35 mol), as is weight uncorrected for a purity of about 85-90%) and DMAC (3320 ml). Nitrogen was bubbled through the resulting dark viscous solution for 40 minutes. To this stirring solution was added Pd2(dba)3 (52.4 g, 57.0 mmol) followed by DPPF (58.4 g, 105 mmol). The resulting slurry was then heated to 85° C. and was treated with solid Zn(CN)2 (372 g, 3.18 mol) portion-wise over a period of 2 hours. The reaction was stirred at 85° C. for 3 hours. At that time the reaction was judged to be complete (by LC and TLC) and was then allowed to cool to 20° C. and stir overnight at that temperature under an atmosphere of N2. The following morning the reaction mixture was split into two equal portions. Each half was diluted with 12 L of water resulting in the formation of a yellow precipitate. The yellow solid from each portion was collected by vacuum filtration rinsing with water (12 L) followed by IPA (500 ml). The combined solids were allowed to air dry in a fume hood to afford 1701 g (1225 g, 85% yield-corrected for a product purity of 72% by weight and a starting material purity of 85%) of a yellow powder. This material was used directly in the next step without purification. TLC Analysis: Rf=0.28 (50% EtOAC/hexanes). HPLC 10:90 to 90:10 CH3CN:H2O over 15 min. Hold at 90:10 for 2 min, 0.025% TFA Buffer, 1.5 mL/min, UV at 220 nm, Phenomenex Jupiter C18 column 4.6 mm×250 mm at 29° C.: (11.68 min, 93 A %) 1H NMR (CDCl3, 300 MHz): 2.70-2.76 (m, 2H), 3.16-3.23 (m, 2H), 4.16 (s, 2H), 4.74 (s, 2H), 7.32-7.45 (m, 5H), 7.98 (s, 1H), 8.69 (s, 1H), 9.30 (br, 1H).

Workup

  1. customA 12 L, 4 neck flask was equipped with an overhead stirrer, an N2 inlet
  2. additionthermocouple, solid addition funnel, and a reflux condenser
  3. customNitrogen was bubbled through the resulting dark viscous solution for 40 minutes
  4. temperatureto cool to 20° C.
  5. stirringstir overnight at that temperature under an atmosphere of N2
  6. customThe following morning the reaction mixture was split into two equal portions
  7. additionEach half was diluted with 12 L of water resulting in the formation of a yellow precipitate
  8. filtrationThe yellow solid from each portion was collected by vacuum filtration
  9. washrinsing with water (12 L)
  10. customto air dry in a fume hood
  11. customto afford 1701 g (1225 g, 85% yield-
  12. customThis material was used directly in the next step without purification
  13. waitHPLC 10:90 to 90:10 CH3CN:H2O over 15 min
  14. waitHold at 90:10 for 2 min
  15. customat 29° C.
  16. custom11.68 min, 93

Sources & evidence

ORD record
ord-825d4c3ecda34ae2b6c480fd0ef04fd2
Source dataset
uspto-grants-2014_08
Patent number
US08809526B2

Reaction notes

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