Phosphorus oxychloride → Ethyl 2-amino-4-chloro-1H-indole-3-carboxylate

HRID 1878513Notes

Reaction equation

HRID 1878513 reaction equation
[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1(Cl)[N+:14]([O-])=O)[C:6]#[N:7])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([O:3][C:4]([C:5]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:21])[NH:14][C:6]=1[NH2:7])=[O:18])[CH3:2]

Participants

3

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 131728954Ethyl(2-chloro-2-nitrophenyl)(cyano)acetate2×

Product 1

HCID 45103996Ethyl 2-amino-4-chloro-1H-indole-3-carboxylate

Procedure

The synthesis route used to prepare analogues is described in Scheme 3. (2-ethoxycarbonylmethyl-phenyl)-acetic acid ethyl ester 2 (71%) was obtained by hydrolysis of 1,2-phenylenediacetonitrile 1 with concentrated H2SO4. Compound 2 with sodium ethoxide in ethanol gave compound 3 (61%), which further reacted with guanidine in the presence of potassium t-butoxide under 150° C. in a microwave reaction to give compound 4 (34%). To access target compounds, first, compound 4 was tried to turn the 4-oxo to 4-chloro, which traditionally is adopted in synthesizing 4-anilino substituted analogues. However, because of the lower aromaticity of the ring, the chlorination did not run well under known reaction conditions. Compound 4 was decomposed when refluxed with POCl3. Thus, the 4-oxo was converted to 4-sulfonate, which is a good leaving group for SNi reaction. Compound 5 was obtained when treating compound 4 with the 4-nitrobenzensulfonyl chloride (36%). The target compound 6 with different substitution on the phenyl ring was obtained when refluxing compound 5 with corresponding aniline for 12-18 h.

Workup

  1. customtraditionally is adopted in synthesizing 4-anilino substituted analogues
  2. customreaction conditions
  3. customfor SNi reaction

Sources & evidence

ORD record
ord-906f90fac3d14c8dabe1da06650f2803
Source dataset
uspto-grants-2012_11
Patent number
US08314114B2

Reaction notes

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