Ammonia → HCID 15094334, compound

HRID 1164255Notes

Reaction equation

HRID 1164255 reaction equation
[Li].[Na].N.[C:4]1([O:10][CH:11]=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=[CH:14]C(Cl)(Cl)Cl>CCOC(C)=O.CC(O)(C)C.C1COCC1>[CH3:14][CH2:11][O:10][CH2:4][CH3:9].[C:4]1([OH:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1

Participants

9

Reactant 5

HCID 222Ammonia2×HCID 6407ChloralHCID 74626Phenyl formateHCID 3028194Lithium2×HCID 5360545Sodium

Product 1

HCID 15094334HCID 15094334, compound

Reagents, catalysts & solvents 3

HCID 6386tert-ButanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

Neutralization to pH 4-5 with concentrated aqueous NH3 and reduction with an equimolar quantity of NaCNBH3 or sodium borohydride in refluxing 45% MeOH (final concentration) for 1.5 h afforded pure (TLC) 7 (86%), mp 199.5°-201.5° C. Birch reduction with lithium or sodium in liquid ammonia of 85 mmol of unpurified 7 with 1.92 g atom of lithium in 450 ml of liquid NH3, 225 mL each of dry THF and t-BuOH at -55° to -65° C. for 4 h, then at -75° C. until no 7 remained by TLC 9 (~1.5 h) afforded (90%) essentially pure (TLC) 8, mp 179.5°-181.5° C. Refluxing unpurified 8 with 1.5 equivalents of pure PhOCHO or chloral in 10 volumes of EtOAc until homogeneous then ~0.75 h until TLC showed absence of 8 gave (94%) pure 10, mp 141°-143° C. (Et2O-PhOH) which, as the N-formyl derivatives described below and others, existed as two distinct rotomers, as shown by NMR. This N-formyl derivative introduces a protective group for the nitrogen in the subsequent steps of the reaction. Compound 7 or 8 may be N-methylated with methyl halide or sulfonate to give compound 9. Stirring a solution of 10 (25° C., 1 h) in 20 volumes of dry THF containing 1% (v/v) CH3SO3H and 3 molar equivalents of ethylene glycol generated a solution of ketal 11 (quantitatively by TLC) which was treated at 0°-5° C. during 0.5 h with 1.05 equivalents of recrystallized N-bromoacetamide (NBA) to afford essentially pure bromoketal 12 after neutralization with NH3 gas, solvent evaporation and workup with CHCl3 -H2O. Bromoketal 12, mp 182.5°-184° C., (EtOAc) could be readily isolated in 88% yield but was most efficiently deketalized in 6 volumes of 5:1 88% HCO2H-H2O (25° C., 1 h) followed by CHCl3 -aqueous NaHCO3 workup to afford 13, mp 203.5°-206.5° C. (DMF-EtOAc), IR (CHCl3) 1717 (C=O) and 1665 (NCHO) cm,-1 in 90% yield from 10.

Workup

  1. customat -75° C.
  2. customremained by TLC 9 (~1.5 h)
  3. customafforded (90%) essentially pure (TLC) 8, mp 179.5°-181.5° C

Sources & evidence

ORD record
ord-ca01672cf3274891942a1e47e458fc21
Source dataset
uspto-grants-1983_01
Patent number
US04368326

Reaction notes

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