Buchwald–Hartwig amination: 6-Chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile → 6-[(1,3-Dimethylpyrazol-4-yl)amino]-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile
55% yield, run at 150 °C, as recorded by experimental reaction archive. The written procedure is below. One of 4 recorded runs making this product; all of them are compared below.
The atoms, from reactants to products
What was in the flask
| Role | Species | Formula | Yield |
|---|---|---|---|
| Reactant | 6-Chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile | C₁₆H₁₃ClN₄O | |
| Reactant | 1,3-dimethyl-1H-pyrazol-4-amine | C₅H₉N₃ | |
| Reagent | sodium phenoxide | C₆H₅NaO | |
| Catalyst | (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine;Ferrocene, 1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)-, (2R)- | C₃₂H₆₂FeP₂ | |
| Catalyst | Palladium (II) acetate | C₄H₈O₄Pd | |
| Solvent | 1,2-Dimethoxyethane | C₄H₁₀O₂ | |
| Product | 6-[(1,3-Dimethylpyrazol-4-yl)amino]-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile | C₂₁H₂₁N₇O | 54.89% |
Conditions
- Temperature
- 150 °C
Yield
- 55% of 6-[(1,3-Dimethylpyrazol-4-yl)amino]-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile.
Every recorded run making this product
4 runs of this class made the same product and differed in what else was in the flask. They are listed from the highest yield down, with this page's run marked.
| Reactants | Catalyst | Reagents | Solvent | Temp. | Time | Yield |
|---|---|---|---|---|---|---|
| 6-Chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile; 1,3-dimethyl-1H-pyrazol-4-amine | (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine;Ferrocene, 1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)-, (2R)-; Palladium (II) acetate | sodium phenoxide | 1,2-Dimethoxyethane | 150 °C | — | 55% (this run) |
| 6-Chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile; 1,3-dimethyl-1H-pyrazol-4-amine | (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine;Ferrocene, 1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)-, (2R)-; Palladium (II) acetate | Cesium carbonate | 1,2-Dimethoxyethane | 150 °C | — | 44% |
| 4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-ylamino)nicotinonitrile; 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one | 1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine); Palladium (II) acetate | Cesium carbonate | 1,4-Dioxane | 100 °C | — | 33% |
| 6-Chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile; 1,3-dimethyl-1H-pyrazol-4-amine | 1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine); Palladium (II) acetate | Cesium carbonate | 1,4-Dioxane | 90 °C | — | 7% |
Procedure
Copied from the source record, unedited
1,3-dimethyl-1H-pyrazol-4-amine (35.5 mg, 0.32 mmol), 6-chloro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (50 mg, 0.16 mmol)sodium phenolate (18.56 mg, 0.16 mmol),(R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T- BUTYLPHOSPHINE (8.74 mg, 0.02 mmol) and diacetoxypalladium (2.87 mg, 0.01 mmol) were suspended in DME (1 mL) and sealed into a microwave tube. The reaction was heated to 150 °C for 30 minutes in the microwave reactor and cooled to RT. LCMS indicated 47% product, ~8% dimer, ~8% hydrolysed Starting material , Starting material 25% and an unknown 17% @ 2.66 and unknown 12% @ 0.77. Sample combined with en01521-027 and en01521-034, SCX'd and sent to purification group. The crude product was purified by preparative basic HPLC. Fractions conta
The source
This record comes from experimental reaction archive (ord-1d37196fb74e494d823157202193321f). Open the source and check it against what is on this page.
experimental reaction archive record ord-1d37196fb74e494d823157202193321f from dataset "750 AstraZeneca ELN dataset" (url: https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471). No atom mapping is provided by the source.
How to read this record
This is one experiment, not a rule. It says that on one occasion these species were combined under these conditions and this came out. It does not say the reaction will give the same result on your substrate, and nothing on the page has been generalised into a claim that it would.
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Where to next
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