Diphenyl Ether → Indole

HRID 1013869Notes

Reaction equation

HRID 1013869 reaction equation
N[C:2]1[NH:7][C:6](=O)[CH:5]=[C:4](Cl)N=1.[C:10]1([O:16]C2C=CC=CC=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[NH:7]1[C:2]2[C:4](=[CH:15][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6]1.[C:10]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1

Participants

4

Reactant 2

HCID 7583Diphenyl EtherHCID 1354033564-Pyrimidinol, 2-amino-6-chloro-

Product 2

HCID 798IndoleHCID 7967Cyclohexanone

Procedure

The synthesis of target compounds commenced from commercially available 2-amino-6-chloropyrimidin-4(3H)-one (1) using a method reported by Taylor et al1 to obtain 2 in 46% yield (Scheme 5). A thermal Fisher Indole-cyclization of 2 and cyclohexanone in diphenyl ether furnished the tricyclic scaffold 3. The partially saturated ring in 3 was oxidized using 10% Pd/C to provide 4 in 57% yield. Pivaloyl protection of 4 gave 5, and subsequent chlorination afforded the synthetic intermediate 6. Compound 6 was treated with various substituted anilines in isopropanal and three drops of concentrated HCl at reflux to provide the penultimate compounds 7-11 in yields of 37 to 80%. The pivaloyl group in 7-11 was removed by a basic hydrolysis of the 2-amide linkage in these compounds using 1N NaOH to give the desired target compounds—AAG103-AAG107 in yields ranging from 64-93%. AAG107 was also synthesized by treating 6 with 3-methoxy-N-methyl aniline, in n-butanol and three drops of conc. HCl at reflux, to afford 16 in a yield of 53%

Workup

  1. customThe synthesis of target compounds
  2. customto obtain 2 in 46% yield (Scheme 5)

Sources & evidence

ORD record
ord-255f33b02e7e4f93a61d0034d685bdf1
Source dataset
uspto-grants-2011_07
Patent number
US07982035B2

Reaction notes

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