Table 3.
HCS catalyst recycling: effect of ligand, leaving group, and alkyne substitution.[a]
|
| ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Entry |
Alkyne |
R2X |
Alkyne [equiv.] |
Ligand [mol %] |
CuI [mol %] |
T [°C] |
Cycle time [h] |
Alkyne addition |
Cycles |
TON final |
Product |
Overall yield[b] [%] |
|
1 |
1 |
2 a |
1.05 |
TPPTS (4) |
0.5 |
30 |
0.5 |
rapid |
10 |
470 |
3 |
94[c] |
|
2 |
1 |
2 a |
1.5 |
TPPDS (4) |
0.5 |
30 |
1 |
rapid |
10 |
465 |
3 |
93 |
|
3 |
1 |
2 a |
1.05 |
TPPMS (4) |
0.5 |
30 |
1 |
rapid |
10 |
475 |
3 |
95 |
|
4 |
6 |
2 a |
1.5 |
TPPTS (4) |
0.5 |
30 |
1 |
rapid |
10 |
460 |
14 |
92 |
|
5 |
7 |
2 a |
1.5 |
TPPTS (4) |
0.5 |
30 |
1 |
rapid |
10 |
470 |
15 |
94 |
|
6 |
8 |
2 a |
1.5 |
TPPTS (4) |
0.5 |
30 |
1 |
rapid |
10 |
475 |
16 |
95 |
|
7 |
9 |
2 a |
1.5 |
TPPTS (4) |
0.5 |
30 |
1 |
rapid |
10 |
480 |
17 |
96 |
|
8 |
10 |
2 a |
1.5 |
TPPTS (4) |
0.5 |
50 |
1 |
rapid |
10 |
465 |
18 |
93[d] |
|
9 |
1 |
2 a |
1.05 |
TPPTS (4) |
– |
60 |
1 |
rapid |
15 |
705 |
3 |
94[c] |
|
10 |
1 |
2 b |
1.05 |
sSphos (4) |
– |
60 |
2 |
2 h |
10 |
470 |
3 |
94 |
|
11 |
1 |
2 b |
1.05 |
sSphos (4) |
0.5 |
30 |
2 |
rapid |
7 |
330 |
3 |
94 |
|
12 |
1 |
11 b |
1.05 |
sSphos (4) |
– |
60 |
2 |
2 h |
10 |
460 |
19 |
92 |
|
13 |
1 |
12 b |
1.05 |
sSphos (4) |
– |
60 |
2 |
2 h |
10 |
475 |
20 |
95 |
|
14 |
9 |
2 b |
1.5 |
sSphos (4) |
– |
60 |
2 |
rapid |
10 |
460 |
17 |
92 |
|
15 |
10 |
2 b |
2 |
sSphos (6) |
– |
60 |
2 |
rapid |
5 |
238 |
18 |
95[d] |
|
16 |
6 |
13 b |
2 |
sSphos (6) |
– |
60 |
3 |
rapid |
8 |
376 |
22 [e] |
94 |
|
17 |
1 |
2 c |
1.05 |
sSphos (6) |
– |
60 |
3 |
3 h |
10 |
480 |
3 |
96 |
|
18 |
1 |
11 c |
1.05 |
sSphos (6) |
– |
60 |
3 |
3 h |
10 |
475 |
19 |
95 |
|
19 |
1 |
12 c |
1.05 |
sSphos (6) |
– |
60 |
3 |
3 h |
10 |
480 |
20 |
96 |
|
20 |
7 |
2 c |
2 |
sSphos (6) |
– |
60 |
2 |
rapid |
10 |
460 |
15 |
92 |
|
21 |
10 |
2 c |
2 |
sSphos (6) |
– |
60 |
2 |
rapid |
7 |
330 |
18 |
94[d] |
[a] All HCS couplings were carried out under nitrogen atmosphere. At the given time the reactions were cooled at RT, extracted with cyclohexane, and the HEP/water phase containing the catalyst was recycled. [b] The combined cyclohexane extracts were distilled and the crude was subsequently purified by flash chromatography generating an average yield. [c] Entries 1 and 9 were carried out also using toluene, 2‐MeTHF, methyl tert‐butyl ether, and isobutyl acetate as extraction solvents giving the same result. [d] Performed with 30 % of water as cosolvent. [e] The work‐up was carried out with toluene and deprotection of the intermediate 21 was directly performed by treatment with NaOH under reflux affording 22 (see the Supporting Information). With quantitative deprotection, yields of 21 and 22 are identical. After deprotection toluene was recovered.