Table 1.
Optimization and regioselectivity for difluoromethylation of β-ketoester 1 a[a]
 | ||||||
|---|---|---|---|---|---|---|
| Entry | 2 c [equiv] | Base (equiv)[b] | Solvent | T [°C] | Yield [%][c] | Ratio 3 a/4 a[d] |
| 1 | 2.0 | P1-tBu (1.5) | CH3CN | RT | 43 | 53:47 |
| 2 | 2.0 | P1-tBu (1.5) | CH2Cl2 | RT | 43 | 53:47 |
| 3 | 2.0 | TMG (1.5) | CH3CN | RT | 34 | 47:53 |
| 4 | 2.0 | DBU (1.5) | CH3CN | RT | 21 | 53:47 |
| 5 | 2.0 | Et3N (1.5) | CH2Cl2 | RT | trace | – |
| 6 | 2.0 | Pyridine (1.5) | CH2Cl2 | RT | trace | – |
| 7 | 2.0 | – | CH2Cl2 | RT | 0 | – |
| 8 | 2.0 | P1-tBu (0.1) | CH2Cl2 | RT | 12 | 58:42 |
| 9 | 2.0 | P1-tBu (1.05) | CH2Cl2 | RT | 30 | 50:50 |
| 10 | 3.0 | P1-tBu (1.5) | CH2Cl2 | RT | 47 | 55:45 |
| 11 | 3.0 | P1-tBu (2.5) | CH2Cl2 | RT | 47 | 55:45 |
| 12 | 3.0 | P1-tBu (1.5) | CH2Cl2 | −78 | 52 | 69:31 |
| 13 | 3.0 | P1-tBu (2.5) | CH2Cl2 | −78 | 68 | 69:31 |
[a]
Reagents and conditions: A solution of 1 a and base, which had been stirred in solvent for 15 min, was added to in situ generated 2 c in CH2Cl2. The mixture was stirred at above given temperature for a further 2–3 h.
[b]
P1-tBu=tert-butylimino-tris(dimethylamino)phosphorane, TMG=tetramethylguanidine, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
[c]
Based on 1 a and determined by 19F NMR using PhCF3 as the internal standard.
[d]
Determined by 19F NMR of the crude products.