Optimization of the reaction conditions for the synthesis of diaryl selenides in the presence of a homogeneous catalyst (CuI)
We started our studies to optimize the C-Se cross-coupling reaction under homogeneous conditions, and iodobenzene and phenylboronic acid were selected as model coupling partners. At first, the reaction was carried out with CuI as a homogeneous catalyst, K2CO3 as a base, and selenium powder as the selenium source in DMSO solvent at 100°C (Table 2, entry 1). Under these conditions, the reaction failed to completely produce the desired unsymmetrical diaryl selenide. Only 65% yield was observed with Na2CO3 as base in this reaction (Table 2, entry 2). Changing the base to Cs2CO3 was not effective for the reaction (Table 2, entry 3). No products were obtained using Et3N as the organic base (Table 2, entry 4). KOH provided the diphenyl selenide product in good to excellent yield (Table 2, entry 5). Also, we investigated how the amount of KOH affects this reaction (Table 2, entry 6). The results showed that 3 mmol KOH was suitable for the desired conversion. Then we investigated the effect of different solvents, such as H2O, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and polyethylene glycol )PEG-200( (Table 2, entries 7–9). Among all the tested solvents, DMSO as solvent gave a satisfying yield (Table 2, entry 5). We then turned our attention to finding the optimal reaction temperature by adjusting it from 80 to 120°C (Table 2, entries 10–11). Lowering the reaction temperature to 80°C resulted in a decrease of the product yield to 65% (Table 2, entry 10), whereas a yield of 95% was achieved at 100°C (Table 2, entry 5). It is important to mention that without a catalyst, the reaction did not take place (Table 2, entry 12). The reaction was investigated in the presence of CuI as a homogeneous catalyst under optimal conditions (Table 2, entry 5). In addition, the effect of other copper salts was also tested. When Cu(OAc)2 and CuCl2 salts were used as catalysts, 55% and 75% yields were obtained, respectively (Table 2, entries 13–14). The amount of the catalyst was also optimized and 50 mg was obtained as the appropriate amount for the reaction (Table 2, entries 15–17).
Table 2
Screening of carbon-selenium bond formation reaction conditions using homogeneous catalyst.
Entry
|
Catalyst type
|
amount of catalyst (mg)
|
Solvent
|
Base (3 mmol)
|
Temp. (°C)
|
Yield (%)a, b
|
1
|
CuI
|
50
|
DMSO
|
K2CO3
|
100
|
80
|
2
|
CuI
|
50
|
DMSO
|
Na2CO3
|
100
|
65
|
3
|
CuI
|
50
|
DMSO
|
Cs2CO3
|
100
|
45
|
4
|
CuI
|
50
|
DMSO
|
Et3N
|
100
|
-
|
5
|
CuI
|
50
|
DMSO
|
KOH
|
100
|
95
|
6
|
CuI
|
50
|
DMSO
|
KOH (1.5 mmol)
|
100
|
80
|
7
|
CuI
|
50
|
H2O
|
KOH
|
reflux
|
N.R
|
8
|
CuI
|
50
|
DMF
|
KOH
|
100
|
55
|
9
|
CuI
|
50
|
PEG200
|
KOH
|
100
|
75
|
10
|
CuI
|
50
|
DMSO
|
KOH
|
120
|
95
|
11
|
CuI
|
50
|
DMSO
|
KOH
|
80
|
65
|
12
|
CuI
|
-
|
DMSO
|
KOH
|
100
|
N.R
|
13
|
Cu(OAc)2
|
50
|
DMSO
|
KOH
|
100
|
55
|
14
|
CuCl2
|
50
|
DMSO
|
KOH
|
100
|
75
|
15
|
CuI
|
70
|
DMSO
|
KOH
|
100
|
94
|
16
|
CuI
|
30
|
DMSO
|
KOH
|
100
|
75
|
17
|
CuI
|
10
|
DMSO
|
KOH
|
100
|
45
|
a Reaction conditions: iodobenzene (1 mmol), phenylboronic acid (1 mmol), Se (1.5 mmol), base (3 mmol), catalyst and solvent (2 mL), b Isolated yield.
Having the optimal reaction conditions (Scheme 3), we explored the variety of aryl halides in this Cu-catalyzed cross-coupling reaction (Table 3). Aryl halides containing electron-donating and electron-withdrawing groups were combined with phenylboronic acid or 4-methylphenylboronic acid to produce unsymmetrical diaryl selenides with good to high yields. As expected, higher yields were obtained under optimal conditions (Table 2, entry 5) for electron-withdrawing aryliodides than electron-donating groups. Also, the results showed that 4-methylphenylboronic acid is more reactive than phenylboronic acid. It is also observed that aryl iodides are more reactive than aryl bromides and chlorides under similar reaction conditions. The selectivity of the synthesis of unsymmetrical diaryl selenides was investigated by testing the reaction of 4-Chlorobromobenzene as a dihalogenated aryl halide. The results showed that the bromide functional group has higher reactivity (Table 3, entry 11).
Based on the results obtained (Table 2, entries 5 and 12) and the previously reported mechanisms 35,61,62, we have proposed a mechanism for the synthesis of unsymmetrical diaryl selenides, which is presented in Scheme 4. We hypothesize that initially the reaction between Se and NaOH occurs and leads to the formation of sodium diselenide 63. Then, sodium diselenide reacts with CuI to form stable copper diselenide. In the next step, the oxidative-addition reaction of copper diselenide with phenylboronic acid creates intermediate A, which is then converted to intermediate B. Then, the key intermediate C is provided by the reaction of intermediate B with aryl halides through cleavage of the C-X bond. Finally, the desired product is obtained through reductive elimination of the C intermediate, restarting the cycle.
Optimization of the reaction conditions for the synthesis of diaryl selenides in the presence of a heterogeneous catalyst (M-MCF@Gua-Cu)
In continuation of our research on forming C-Se bonds, we investigated synthesis of unsymmetrical diaryl selenides by reacting aryl halides with phenylboronic acid or 4-methylphenylboronic acid, Se powder, and the recoverable magnetic nanocatalyst M-MCF@Gua-Cu. Our research started by using iodobenzene and phenylboronic acid as reactants to improve the reaction parameters. (Table 4). To determine the amount of nanocatalyst, it was natural to try smaller amounts of catalyst. When the amount of M-MCF@Gua-Cu was decreased from 50 to 10 mg, a decrease in product yield was observed (Table 4, entries 1–4). As a result, the amount of 30 mg was chosen as the optimal amount, and more amounts of catalyst did not significantly impact the reaction yield. Next, we examined how the solvent impacts the reaction by testing different solvents like DMF, H2O, DMSO, Dioxane, and PEG-200 (Table 4, entries 5–8). When DMSO was used as the solvent, 80% product yield was observed. When the reaction was performed in PEG-200 (Table 4, entry 3) using the same reaction conditions, the product yield increased to 94%. A significant amount of the diaryl selenide product was obtained when K2CO3 was employed as the base (Table 4, entry 10). Additionally, the product yield increased to 94% by using KOH in the reaction, while keeping other reaction conditions constant (Table 4, entry 3). We then turned our attention to finding the optimal reaction temperature by adjusting it from 90 to 130°C (Table 4, entries 13–14). The yield of the product decreased with decreasing reaction temperature, while a yield of 94% was obtained when the reaction was carried out at 120°C (Table 4, entry 3).
Table 4
Screening of carbon-selenium bond formation reaction conditions using heterogeneous catalyst.
Entry
|
Catalyst (mg)
|
Solvent
|
Base (4 mmol)
|
Temp. (°C)
|
Yield (%)a, b
|
1
|
-
|
PEG200
|
KOH
|
120
|
N.R
|
2
|
50
|
PEG200
|
KOH
|
120
|
95
|
3
|
30
|
PEG200
|
KOH
|
120
|
94
|
4
|
10
|
PEG200
|
KOH
|
120
|
70
|
5
|
30
|
DMF
|
KOH
|
120
|
65
|
6
|
30
|
DMSO
|
KOH
|
120
|
80
|
7
|
30
|
H2O
|
KOH
|
reflux
|
N.R
|
8
|
30
|
Dioxane
|
KOH
|
reflux
|
N.R
|
9
|
30
|
PEG200
|
NaOH
|
120
|
70
|
10
|
30
|
PEG200
|
K2CO3
|
120
|
75
|
11
|
30
|
PEG200
|
Na2CO3
|
120
|
65
|
12
|
30
|
PEG200
|
KOH (2 mmol)
|
120
|
75
|
13
|
30
|
PEG200
|
KOH
|
130
|
95
|
14
|
30
|
PEG200
|
KOH
|
90
|
80
|
a Reaction conditions: iodobenzene (1 mmol), phenylboronic acid (1 mmol), Se (1.5 mmol), base (4 mmol), catalyst and solvent (2 mL), b Isolated yield.
Under optimal conditions (Scheme 5), we studied the coupling reaction of different aryl halides and phenylboronic acid or 4-methylphenylboronic acid using the M-MCF@Gua-Cu magnetic nanocatalyst (Table 5). The corresponding diaryl selenides were synthesized with good to high yields, ranging from 70–94%, as shown in Table 5. Among the different types of aryl halides, it is worth noting that aryl iodides show the highest levels of reactivity, as shown in Table 5. It is interesting to observe that even aryl bromides and chlorides, which are considered to be less reactive substrates, can still be converted to the corresponding unsymmetrical diaryl selenides with good to high yields under similar reaction conditions. It was observed that aryl halides containing electron-donating groups underwent a slow conversion. Aryl halides containing electron-withdrawing groups showed good reactivity. In addition, to investigate the selectivity of this system, the reaction of dihalogenated 4-Chlorobromobenzene was studied in heterogeneous conditions. The test results showed that the bromide functional group exhibited a higher level of reactivity (Table 5, entry 11).
Reusability of the catalyst
In addition to showing high catalytic performance, the cyclability of heterogeneous catalysts represents a great advantage. To achieve this, the catalytic recycling experiment was conducted using the reaction of iodobenzene and phenylboronic acid as model reactions. After each run, the nanocatalyst was recovered with a magnetic instrument, washed with ethanol, dried before use, and its efficiency was evaluated in the next step. The above procedure was repeated, finding that the nanocatalyst could be reused more than five times without significant decrease in its performance (Fig. 11).