Ammonia → 6-Azaindole

HRID 1851073Notes

Reaction equation

HRID 1851073 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=C[CH:8]=2)[CH:3]=[CH:2]1.C1(CC([NH2:19])=O)C=CC=CC=1.CC(C)([O-])C.[K+].N.N1C2C(=CC=CC=2)C=N1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C([N+]([O-])=O)=CC=CN=1.[N+](C1C=NC=CC=1Cl)([O-])=O.C([Mg]Br)=C>O.O1CCOCC1.O1CCCC1.CCOCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[N:19][CH:8]=2)[CH:3]=[CH:2]1

Participants

14

Reactant 9

HCID 222AmmoniaHCID 798Indole3×HCID 7680BenzeneacetamideHCID 92211H-IndazoleHCID 796132-Chloro-3-nitropyridineHCID 27357814-Chloro-3-nitropyridineHCID 6451240Aluminum(III) ChlorideHCID 23665647Potassium tert-butoxideHCID 178418507HCID 178418507, compound

Product 1

HCID 92196-Azaindole

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Procedure

An indole glyoxyl ester is reacted with a phenyl acetamide derivative in a one-pot reaction in an inert solvent in the presence of a strong base. Preferably an ether is used as an inert solvent, such as tetrahydrofurane or dioxane. As a base potassium tert.-butoxide can for example be used. The water formed during the reaction is removed, for example by using a molecular sieve. The phenyl acetamides used as starting material are readily available from the corresponding acetic acids which are converted to the acid chloride and hydrolyzed with ammonia. The indole glyoxyl esters (R=methyl, ethyl) can be synthesized by Friedel-Crafts-type acylation of the corresponding indole derivative with methyl or ethyl oxalyl chloride, cf. Tetrahedron 1999, 55 (43), 12577-12594. The corresponding azaindole glyoxyl esters can be prepared according to the method reported in J. Org. Chem. 2002, 67: 6226-6227 or by Friedel-Crafts acylation in the presence of aluminum chloride, cf. Organic Letters (2000) vol. 2, no. 10, 1485-1487. The 4- and 6-azaindole starting compounds can be prepared by reacting 2-chloro-3-nitropyridine or 3-nitro-4-chloropyridine with vinyl magnesium bromide to give the 7-chloro-substituted 4- or 6-azaindole. The chloro substituent is then removed by catalytic hydrogenation. Said reactions are carried out as described in J. Org. Chem. 67: 2345-2347 (2002) and J. Heterocycl. Chem. 29: 359-363 (1992). The 4-aza-indole starting compound can also be synthesized according to the procedures disclosed in Org. Biomol. Chem. 3, 20, 3701-3706 (2005).

Sources & evidence

ORD record
ord-7143adcf863e4075adb6839529afb607
Source dataset
uspto-grants-2015_02
Patent number
US08957103B2

Reaction notes

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