Dimethylacetamide → (1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide

HRID 1623963Notes

Reaction equation

HRID 1623963 reaction equation
[OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:26][C@H:15]3[C:16]=2[N:17]([C:19]2[CH:24]=[C:23](Br)[CH:22]=[CH:21][N:20]=2)[N:18]=1)=[O:10])[C:4]([CH3:7])([CH3:6])[CH3:5].C[C:28]([N:30](C)C)=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N>[OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:26][C@H:15]3[C:16]=2[N:17]([C:19]2[CH:24]=[C:23]([C:28]#[N:30])[CH:22]=[CH:21][N:20]=2)[N:18]=1)=[O:10])[C:4]([CH3:7])([CH3:6])[CH3:5]

Participants

5

Reactant 2

HCID 31374DimethylacetamideHCID 86669700(1aR,5aR)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide

Product 1

HCID 123483012(1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid ((S)-1-Hydroxymethyl-2,2-dimethyl-propyl)-amide

Reagents, catalysts & solvents 2

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

(1aR,5aR)-2-(4-Bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (2.38 g, 5.68 mmol) was dissolved in DMA (10 mL). Nitrogen was bubbled through the solution for 20 min. Zinc(II) cyanide (1.333 g, 11.35 mmol) and palladium tetrakistriphenylphosphine (0.328 g, 0.284 mmol) were added. The reaction was heated under microwave at 120° C. for 1 h. The reaction was diluted with 100 mL ethyl acetate, filtered, then concentrated. The residue was purified by silica gel column chromatography and then crystallized from EtOAc/hexanes to give the title compound as a white solid (1.78 g). LCMS m/z=366.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.45 (td, J=4.7, 3.3 Hz, 1H), 1.06 (s, 9H), 1.25 (td, J=8.0, 4.9 Hz, 1H), 2.26-2.32 (m, 1H), 2.35 (t, J=5.5 Hz, 1H), 2.78-2.83 (m, 1H), 2.93 (d, J=17.2 Hz, 1H), 3.03 (dd, J=16.7, 6.3 Hz, 1H), 3.66-3.72 (m, 1H), 3.94-4.01 (m, 2H), 7.01 (d, J=8.6 Hz, 1H), 7.41 (dd, J=5.1, 1.4 Hz, 1H), 8.15 (dt, J=1.1 Hz, 1H), 8.62 (dd, J=5.1, 0.8 Hz, 1H).

Workup

  1. customNitrogen was bubbled through the solution for 20 min
  2. filtrationfiltered
  3. concentrationconcentrated
  4. customThe residue was purified by silica gel column chromatography
  5. customcrystallized from EtOAc/hexanes

Sources & evidence

ORD record
ord-d852b06e86c646edb17625fdbc0cbbb6
Source dataset
uspto-grants-2014_07
Patent number
US08778950B2

Reaction notes

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