Potassium Carbonate → 5-(3,3-dimethyl-but-1-ynyl)-3-(N'-methyl-N'-pyridin-2-yl-hydrazino)-thiophene-2-carboxylic acid methyl ester

HRID 39313Notes

Reaction equation

HRID 39313 reaction equation
[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1I)=[O:4].[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:19][N:18]([CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:4]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 77911Pyridine, 2-(1-methylhydrazinyl)-HCID 581139365-(3,3-Dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid methyl ester

Product 1

HCID 673209805-(3,3-dimethyl-but-1-ynyl)-3-(N'-methyl-N'-pyridin-2-yl-hydrazino)-thiophene-2-carboxylic acid methyl esterYield 50%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 5-(3,3-dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.28 mmol), N,N-diethylenediamine (9 μL, 0.086 mmol), N-methyl-N-pyridin-2-yl-hydrazine (0.105 g, 0.86 mmol), CuI (0.01 g, 0.057 mmol), 4 Å ms (0.114 mg) and K2CO3 (0.118 g, 0.861 mmol) in DMF (3 mL) was heated to 80° C. for 16 h. The reaction was diluted with ethyl acetate, washed twice with 5% LiCl, concentrated and the crude material was purified by silica gel chromatography (0-20% EtOH in DCM) to give 5-(3,3-dimethyl-but-1-ynyl)-3-(N′-methyl-N′-pyridin-2-yl-hydrazino)-thiophene-2-carboxylic acid methyl ester in 50% yield. This was then dissolved in pyridine (5 mL) and treated with neat trans-4-methyl-cyclohexanecarbonyl chloride (0.132 g, 0.825 mmol). The reaction was heated for 16 h at 85° C. and quenched with saturated ammonium chloride solution. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude material was then dissolved in a 3:2:1 mixture of THF:MeOH:water (5 mL), treated with lithium hydroxide monohydrate (0.69 g, 1.65 mmol) and heated to 60° C. for 1 hour. The organic volatiles were evaporated under reduced pressure and the crude material was purified by HPLC to afford the title compound. MS (m/z): 454.1 [M+H]−; HPLC retention time: 3.95 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).

Workup

  1. washwashed twice with 5% LiCl
  2. concentrationconcentrated
  3. customthe crude material was purified by silica gel chromatography (0-20% EtOH in DCM)

Sources & evidence

ORD record
ord-15f78fb80e204846958d9219e0e74464
Source dataset
uspto-grants-2013_09
Patent number
US08524764B2

Reaction notes

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