Buchwald–Hartwig amination: 4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-ylamino)nicotinonitrile → 6-[(1,3-Dimethylpyrazol-4-yl)amino]-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile
33% yield, run at 100 °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 | 4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-ylamino)nicotinonitrile | C₁₁H₁₀ClN₅ | |
| Reactant | 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one | C₁₀H₁₂N₂O | |
| Reagent | Cesium carbonate | CCs₂O₃ | |
| Catalyst | 1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine) | C₃₉H₃₂OP₂ | |
| Catalyst | Palladium (II) acetate | C₄H₈O₄Pd | |
| Solvent | 1,4-Dioxane | C₄H₈O₂ | |
| Product | 6-[(1,3-Dimethylpyrazol-4-yl)amino]-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile | C₂₁H₂₁N₇O | 33.24% |
Conditions
- Temperature
- 100 °C
Yield
- 33% 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% |
| 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% (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 | 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
8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (35.6 mg, 0.20 mmol), 4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-ylamino)nicotinonitrile (25 mg, 0.10 mmol), diacetoxypalladium (1.133 mg, 5.05 µmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.84 mg, 10.09 µmol) and cesium carbonate (39.5 mg, 0.12 mmol) were dissolved in dioxane (0.5 mL) and sealed into a microwave tube. nitrogen was let to bubble into the mixture then the reaction was heated to 100 °C for 90 minutes. Crude LCMS showed the expected product P3 and no hydrolysis by-product at all like in _EN01775-20_ !! The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml / minute) and decreasingly polar mixt
The source
This record comes from experimental reaction archive (ord-0b6cfa905b6344a5ad945299463325fe). Open the source and check it against what is on this page.
experimental reaction archive record ord-0b6cfa905b6344a5ad945299463325fe 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.
The pathway is a separate question, kept on separate pages. A mechanism here is the canonical arrow pushing for a class, run on real structures and labelled rule-derived. It is not evidence, and this record is not a mechanism.
Where to next
More Buchwald–Hartwig amination records
Other runs of this class, one page per distinct transformation.
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