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entree SiliaCat

Suzuki Coupling Using Pd-based SiliaCat

The Suzuki coupling (also called Suzuki-Miyaura reaction) is the reaction between a boronic acid and a halide catalyzed by a palladium (0) catalyst widely used in organic synthesis. At first, only aryl and vinyl substrates could undergo Suzuki coupling. Now, catalysts are becoming so powerful that the substrate scope has broadened to include: alkyl-, alkenyl- & alkynyl- halides, triflates and organoboranes, trifluoroborates or borate esters.
Its discovery was awarded the Nobel Prize in Chemistry in 2010.

CycleSuzukiCoupling.gif

 

Solvent and Base Effects

The choice of solvent and base play an important part in the Suzuki reaction. Different solvents and bases were tested to find the most suitable combination. Total conversion was obtained in both ethanol and propanol. With THF, dioxane, toluene and DMF, the kinetics were lower.

For the base, potassium carbonate (K2CO3) is the best. However, in some cases, Na2CO3 and NaOAc can also be used.

Suzukireaction1.gif

Solvent and Base Effects
Solvent Temp.
(°C)
Conversion / Selectivity (%)
K2CO3 Na2CO3 KOAc NaOAc K2HPO4 Et3N
MeOH 64 74 / 95 69 / 99 63 / 98 63 / 98 73 / 100 72 / 93
EtOH 77 100 / 98 100 / 97 82 / 99 85 / 100 79 / 100 77 / 93
EtOH/H2O (15%) 77 100 / 100 82 / 100 78 / 100 88 / 100 86 / 98 89 / 95
1-PrOH 90 100 / 95 70 / 97 90 / 99 91 / 99 15 / 100 20 / 95
2-PrOH 77 100 / 100 43 / 93 90 / 99 72 / 100 50 / 100 20 / 100
THF 64 30 / 93 15 / - 45 / 89 35 / 94 37 / 95 5 / -
MeTHF 77 40 / 95 33 / 100 39 / 100 56 / 100 30 / 97 4 / -
Dioxane 90 50 / 90 30 / 93 56 / 93 35 / 94 20 / 90 No reaction
Toluene 90 47 / 98 23 / 87 49 / 96 10 / 90 65 / 95 No reaction
DMF 90 50 / 100 30 / 100 15 / 100 17 / 100 7 / 100 No reaction

 

Catalyst Concentration Effect

Decreasing the mol % of the catalyst lowers the kinetics of the reaction, but the total conversion can still be achieved. In this example, the addition of water significantly improves catalyst activity. Even if the catalyst amount is divided by 10, the TOF is still increased by a factor of five.

(Cdns: SiliaCat DPP-Pd, PhB(OH)2 (1.1 eq.), K2CO3 (1.5 eq.) RT).

Catalyst Concentration Effect
mol % Solvent (M) Time (h) Conv. (%) TON TOF
0.2 EtOH (0.05) 0.5 100 500 1,000
0.1 EtOH (0.05) 1 100 1,000 1,000
0.01 EtOH/H2O (0.08) 2 100 10,000 5,000
0.002 EtOH/H2O (0.08) 16 100 50,000 3,125

 

Pd-Based SiliaCat’s Catalytic Performance Comparison and Reusability

All SiliaCat Pd-based catalysts can be used for Suzuki coupling. The table below presents the best conditions for bromo- substrates. It can be seen that even with half the catalyst amount, SiliaCat Pd0 is the more active catalyst.

For substrates with electron-withdrawing groups, SiliaCat catalysts can be reused more than 5 times with a minimal loss of activity and leaching. For substrates containing an electron-donating group, SiliaCat catalysts can be used up to 3 times with only a small effect on activity.

Pd-Based SiliaCat's Catalytic Performance Comparison and Reusability
Substrate (R)
SiliaCat Performance Comparaison
[Conversion / Selectivity (%)]
Reusability [Conversion / Selectivity (%)]
Pd & Si Leaching (ppm)1
DPP-Pd
(1 mol %)a-b
S-Pd
(1 mol %)c
Pd0
(0.5 mol %)d
Run 2
Run 3
Run 4
Run 5
Electron-Withdrawing
ParallelSubstrat1.gif
100 / 100
Pd: 0.1, Si: 2
100 / 99
100 / 99
100 / 100
Pd: 0.05, Si: 1
100 / 100
Pd: 0.08, Si: 1.5
100 / 100
Pd: 0.1, Si: 3
99 / 98
Pd: 0.1, Si: 3.5
ParallelSubstrat2.gif
100 / 97
Pd: 0.1, Si: 3
100 / 99
99 / 97
98 / 99
Pd: 0.1, Si: 8
98 / 99
Pd: 0.07, Si: 5
100 / 99
Pd: 0.1, Si: 6
99 / 98
Pd: 0.1, Si: 5
ParallelSubstrat3.gif
100 / 97
Pd: 0.1, Si: 6
94 /88
95 / 98
99 / 90
Pd: 0.2, Si: 7
97 / 92
Pd: 0.2, Si: 8
99 / 98
Pd: 0.1, Si: 4
98 / 97
Pd: 0.1, Si: 5
Electron-Donating
ParallelSubstrat4.gif
100 / 99
Pd: 0.9, Si: 5
82 / 100
83 / 100
100 / 100
Pd: 0.6, Si: 9
100 / 98
Pd: 0.4, Si: 7
60 / 97
Pd: 0.05, Si: 6
-
ParallelSubstrat5.gif
100 / 80
Pd: 0.07, Si: 3
94 / 100
98 / 99
99 / 99
Pd: 0.04, Si: 1.5
98 / 98
Pd: 0.1, Si: 2
81 / 94
Pd: 0.06, Si: 2
73 / 95
Pd: 0.03, Si: 7
ParallelSubstrat6.gif
100 / 99
Pd: 2.1, Si: 10
72 / 95
97 / 95
88 / 90
Pd: 0.3, Si: 7
75 / 95
Pd: 4, Si: 9
87 / 99
Pd: 0.6, Si: 10
68 / 96
Pd: 04, Si: 11
aCorresponds to "Run 1" in the reusability study.
General exp. cond.: 1 eq. substrate, 1.2 eq. PhB(OH)2, 2 eq. K2CO3; b MeOH (0.1 M), 2 h, 65°C; c EtOH/H2O (0.12 M) 4h, 77°C; d EtOH (0.12 M) 2h, 77°C.
1Using SiliaCat DPP-Pd as catalyst under the same conditions previously described. Run #1 is the result presented in the performance comparison section of the table.

 

The performance of the SiliaCat DPP-Pd and S-Pd catalysts for Suzuki coupling was also compared in microwave assisted experiments for brominated substrates. Both products exhibit a very high performance in microwave experiments. After only 5 minutes, 100% of the product is obtained in most experiments. Both also present high selectivity, with yields nearly reaching 100%. The products were also tested for chlorinated substrates as presented on the following page.

Catalytic Performance in Microwave
Substrate (R)
Conversion (%) / Yield (%)
SiliaCat DPP-Pd
(0.5 mol %)a-b
SiliaCat S-Pd
(0.5 mol %)c
ParallelSubstrat1.gif
100 / 99.5
100 / 99.3
ParallelSubstrat2.gif
100 / 99.4
100 / -
ParallelSubstrat3.gif
100 / 88
100 / -
ParallelSubstrat4.gif
98 / 97.3
72 / -
General exp. cond.: 1 eq. substrate, 1.1 eq. PhB(OH)2, 1.5 eq. K2CO3; aMeOH (0.2 M), 5 min, 75°C, 150 W, 150 psi; bMeOH (0.2 M), 5 min, 75°C, 200 W, 200 psi, c15 min.

 

The SiliaCat Pd-based catalysts can also be used for Suzuki coupling with chlorinated substrates in both conventional and microwave conditions. We have chosen to do this study with SiliaCat DPP-Pd.

Catalytic Performance of Chlorinated Substrates
Substrate (R)
Conversion /Yield (%)a
Substrate (R)
Conversion /Yield (%)a
ParallelSubstrat7.gif
98 / 93
ParallelSubstrat9.gif
99 / -
ParallelSubstrat8.gif
98 / 96
ParallelSubstrat10.gif
Bulk: 100 / 98
MWb: 100 / 95
aExp. cond. in bulk: 1.5 mol % of SiliaCat, 1 eq. substrate, 1.5 eq. PhB(OH)2, 2 eq. K2CO3,
EtOH/H2O 15% (0.12M), 6 h, reflux. bMicrowave: 1 mol % of SiliaCat, 15 min, 125°C.

 

Conclusion for Suzuki Coupling

In conclusion, SiliaCat, can be used successfuly for Suzuki coupling reactions with iodide, bromide and chloride aryl substrates in conventional or in microwaves conditions. The SiliaCat DPP-Pd gives better performance versus the SiliaCat S-Pd and nearly equivalent to the SiliaCat Pd0 for the substrates presented.

 

Suzuki Coupling Typical Experimental Condition

Conventional Experimental Conditions

Reaction - All products except the catalyst are added to a round bottom flask equipped with a condenser and a magnetic stirrer. Bring mixture to reflux and, after 10 minutes (when the solution is homogeneous), add the required quantity of catalyst.

Microwave Conditions

Reaction - All products are added to a microwave tube equipped with a magnetic stirrer. Set microwave conditions to:

  • Power: 150 W
  • Pressure: 150 psi
  • Temperature: 75 - 150°C
  • Reaction Time: 5 - 15 min

Work-up

Once the reaction is complete (determined by TLC or GC-MS), the catalyst is filtered at room temperature, rinsed twice with water and three times with the solvent used in the reaction, and finally dried and stored for future use. The reaction mixture obtained after filtration of the catalyst is evaporated, and the product is extracted using ethyl acetate (AcOEt) or diethyl ether (Et2O) and washed twice with water. The organic phase is dried using magnesium sulfate (MgSO4), and filtered, and the solvent is evaporated. The crude mixture is purified using flash chromatography, if needed. Also applicable to microwave conditions.

Suzuki Coupling Typical Experimental Conditions
Products
Conventional Conditions
Microwave Conditions
Ar-Iodide
Ar-Bromide
Ar-Chloride
Ar-Iodide
Ar-Bromide
Ar-Chloride
Base [K2CO3]
1.5 eq.
1.5 eq.
2.0 eq.
1.5 eq.
1.5 eq.
2.0 eq.
Boronic Acid
1.2 eq.
1.2 eq.
1.5 eq.
1.2 eq.
1.2 eq.
1.5 eq.
SiliaCat Catalyst
≥ 0.5 mol %
≥ 0.5 mol %
≥ 1.0 mol %
≥ 0.5 mol %
≥ 0.5 mol %
≥ 1.0 mol %
Best Solvents
(HPLC Grade)
MeOH
(0.05 - 0.1 M)
EtOH/H2O
(10:1, 0.12 M)
EtOH or TBA/H2O
(10:1.5, 0.12 M)
MeOH
(0.2 M)
MeOH
(0.2 M)
EtOH/H2O
(10:1, 0.2 M)
*Note: molar concentration is related to the substrate.

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  1. SiliaCat DPP-Pd heterogeneous catalyst

    SiliaCat® Heterogeneous Catalysts DPP-Pd

    Typical Applications: Suzuki, Heck, Sonogashira, Kumada, Stille and Buchwald amination
  2. SiliaCat® Heterogeneous Catalysts TEMPO

    SiliaCat® Heterogeneous Catalysts TEMPO

    Typical Applications: Oxidation of alcohols or Aldehydes
  3. SiliaCat® Heterogeneous Catalysts Pd0

    SiliaCat® Heterogeneous Catalysts Pd0

    Typical Applications: Suzuki, Heck Sonogashira, Kumada, Stille, Selective debenzylation, Selective hydrogenation
  4. SiliaCat® Heterogeneous Catalysts Pt0

    SiliaCat® Heterogeneous Catalysts Pt0

    Typical Applications: Selective reduction of nitroarenes, Hydrosilylation
  5. SiliaCat® complete heterogeneous catalysts kit: SiliaCat DPP-Pd, SiliaCat Pd0, SiliaCat Pt0 and SiliaCat TEMPO

    SiliaCat® complete heterogeneous catalysts kit

    Containing SiliaCat DPP-Pd, SiliaCat Pd0, SiliaCat Pt0 and SiliaCat TEMPO

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