Table 1.
Reaction optimization.
| entry | equiv 1 | base (equiv) | catalyst mol% |
mol% NH2OH•HCI | equiv n-BuNH2 | solvent | time (h) | isolated yield (%) |
|---|---|---|---|---|---|---|---|---|
| R = −CH2CH2Ph (a) | ||||||||
| 1 | — | NaH (2.0) | — | — | — | — | — | —b |
| 2 | 2.0 | TBAF•3H2O (10) | CuCl (20) | 30 | 30 | DMF | 24 | 0 |
| 3 | 2.0 | LiHMDS (2.0) | CuCl (20) | 30 | 2 | DMF | 24 | 21 |
| 4 | 2.0 | LiHMDS (2.0) | CuCl (2) | 0 | 2c | DMF | 24 | 0 |
| Pd(dba)2 (4) | ||||||||
| 5 | 2.0 | LiHMDS (2.0) | CuCl (20) | 30 | 2 | THF | 18 | 14 |
| Pd(dba)2 (4) | ||||||||
| 6 | 2.0 | LiHMDS (2.0) | CuCl (50) | 150 | 10 | THF | 18 | 28 |
| 7 | 2.0 | LiHMDS (2.0) | CuCl (20) | 30 | 10 | H2O/THF | 18 | 49 |
| 8 | 2.0 | LiHMDS (2.0) | CuCl (20) | 30 | 20 | H2O/THF | 3 | 80 |
| R = −CH3 (b) | ||||||||
| 9 | 2.0 | LiHMDS (2.0) | CuCl (20) | 30 | 20 | H2O/THF | 18 | 44 |
| 10 | 2.5 | LiHMDS (2.5) | CuCl (20) | 30 | 20 | H2O/THF | 1 | 27 |
| 11 | 1.0 | LiHMDS (1.0) | CuCl (20) | 30 | 20 | H2O/THF | 1 | 57 |
| 12 | 1.5 | LiHMDS (1.5) | CuCl (20) | 30 | 20 | H2O/THF | 1 | 69 |
| 13 | 1.5 | LiHMDS(1.5) | CuCl (40) | 60 | 20 | H2O/THF | 1 | 72 |
a
Elimination conditions: NaH: THF, 0 to 23 °C, 24 h; TBAF•3H2O: DMF, 60 °C, 3 h; LiHMDS: THF, −78 to 0 °C, 1.5 h.
b
Bromoalkyne intermediate 2a was not observed; coupling was not attempted.
c
Et3N used as base instead of n-BuNH2.