SusChemE 2015
International Conference on Sustainable Chemistry & Engineering
October 8-9, 2015, Hotel Lalit, Mumbai
Palladacycle Catalyzed Carbonylative Suzuki‒Miyaura Coupling with
High Turnover Number and Turnover Frequency
Prashant Gautam1, Bhalchandra M. Bhanage1
1
Department of Chemistry, Institute of Chemical Technology, N.P. Marg, Matunga‒400019,
Mumbai, India.
E-mail addresses: gautam.prshant@gmail.com, bm.bhanage@gmail.com
1. Introduction:
The carbonylative Suzuki‒Miyaura coupling utilizing carbon monoxide as the C1 source is one of the pivotal reactions for the
synthesis of biaryl ketones. Biaryl ketones are important structural building blocks present in a wide variety of molecules which
include pharmaceutical drugs, natural products, and sunscreen agents. These biaryl ketones have been synthesized through
carbonylative Suzuki‒Miyaura coupling using variety of palladium catalysts and the reaction using aryl iodides is well
documented in the literature. The main drawbacks of these catalytic systems include high palladium loading, poor turnover
numbers (TON’s) and turnover frequencies (TOF’s) and the need to handle air and moisture sensitive phosphine ligands.
Palladacycles have been reported exhaustively for the conventional cross‒coupling reactions (Heck, Suzuki, Sonogashira,
Buchwald‒Hartwig) and have been shown to produce extremely high TON’s and TOF’s vis‒à‒vis conventional palladium
sources. The fact that they are air and moisture stable is an added advantage.
2. Material and Methods:
Bedford’s palladacycle 2 was used to carry out the reaction optimization followed by a study to determine the lowest palladium
loading possible to generate the desired product. It was also used to carry out a substrate scope study. The dinorbornyl complex 1
and RuPhos 3 were screened for relative comparison amongst palladacyclic complexes as well as with Pd(OAc) 2. A scale up
study at gram scale at was also carried out. The optimization reactions were monitored by GC analysis and the substrates were
isolated and characterized by GC-MS, 1H and 13C NMR.
3. Significant Results and Discussion
The results of the experiments are presented in this section.
1
SusChemE 2015
International Conference on Sustainable Chemistry & Engineering
October 8-9, 2015, Hotel Lalit, Mumbai
3.1 Optimization of reaction:
Table 1. Optimization of reaction.
CO
Base
Time
Yielda
pressure
(h)
(%)
(bar)
Effect of CO pressure
1
1
K2CO3
5
89
2
2
K2CO3
5
95
3
3
K2CO3
5
65
Effect of base
4
2
K2CO3
5
95
5
2
Na2CO3
5
66
6
2
Et3N
5
74
7
2
K3PO4
5
70
Effect of time
8
2
K2CO3
1
41
9
2
K2CO3
3
79
10
2
K2CO3
6
95
Reaction conditions: 4a (0.5 mmol), 5a (0.75 mmol), 2 (0.1 mol%), base (1.5 mmol), anisole (11 mL). a GC yield.
Entry
3.2 Effect of catalyst loading, time and temperature:
Table 2. Effect of catalyst loading, time and temperature.
BZe
TOF
2
Entry
mol
(%)
TONf
(h−1)
%
1
2
3
4
5a
6b
7b
8b
9c
10d
11d
10−1
10−2
10−3
10−4
10−4
10−4
10−5
10−6
10−7
10−8
10−9
98
97
95
84
91
95
93
88
54
48
10
4.90 × 102
4.85 × 103
4.75 × 104
4.20 × 105
4.55 × 105
4.75 × 105
4.65 × 106
4.50 × 107
2.70 × 108
2.40 × 109
5.00 × 109
0.98 × 102
9.70 × 102
9.50 × 103
8.40 × 104
9.10 × 104
9.50 × 104
9.30 × 105
9.00 × 106
5.40 × 107
4.80 × 108
1.00 × 109
Standard reaction conditions: 4a (0.5 mmol), 5a (0.75mmol), K2CO3 (1.5 mmol), CO (2 bar), anisole (11 mL) at 80 °C for 5
h. a 12 h. b 120 °C. c 140 °C. d 160 °C. e GC yield (calculated as an average of triplicate measurements). f mol product per mol
Pd. BZ‒benzophenone.
3.3 Scope of the palladacycle catalyzed carbonylative Suzuki‒Miyaura coupling:
Table 3. Scope of the palladacycle catalyzed carbonylative Suzuki‒Miyaura coupling.
2
SusChemE 2015
International Conference on Sustainable Chemistry & Engineering
October 8-9, 2015, Hotel Lalit, Mumbai
Entry
1
2
3
4
5
6
7a
8a
9a
10a
11a
12b
13b
14b
15b
16b
4
R1 = 4‒OCH3 (4b)
R1 = 4‒NH2 (4c)
R1 = 2‒NH2 (4d)
R1 = 3‒NO2 (4e)
R1 = 4‒CN (4f)
1‒naphthyl (4g)
4c
4f
4b
4e
2‒pyridyl (4h)
2‒pyridyl (4h)
2‒thienyl (4i)
4a
4i
4i
17b
4i
5
R2 = H (5a)
R2 = 4‒F (5b)
R2 = 4‒Cl (5c)
R2 = 3‒Me (5d)
5d
5b
5a
5a
5a
3‒thienyl (5e)
5e
R2 = 4‒OCH3
(5f)
5c
6/Yieldc
6b/89
6c/94
6d/69
6e/80
6f/88
6g/90
6h/81
6i/90
6j/86
6k/85
6l/71
6l/89
6m/88
6n/85
6o/80
6p/82
TONd
4.45 × 107
4.70 × 107
3.45 × 107
4.00 × 107
4.40 × 107
4.50 × 107
4.05 × 106
4.50 × 106
4.30 × 106
4.25 × 106
3.55 × 106
4.45 × 104
4.40 × 104
4.25 × 104
4.00 × 104
TOF (h−1)
8.90 × 106
9.40 × 106
6.90 × 106
8.00 × 106
8.80 × 106
9.00 × 106
8.10 × 105
9.00 × 105
8.60 × 105
8.50 × 105
7.10 × 105
3.70 × 103
3.66 × 103
3.54 × 103
3.33 × 103
4.10 × 104
3.41 × 103
6q/93
4.65 × 104
3.87 × 103
Reaction conditions: aryl iodide (0.5 mmol), aryl boronic acid (0.75 mmol), K2CO3 (1.5 mmol), [Pd, 2] (10−6 mol%), CO (2
bar), anisole (11 mL) at 120 °C for 5 h. a [Pd, 2] (10−5 mol%). b [Pd, 2] (10‒3 mol%), CO (5 bar) for 12 h c Yield. d mol
product per mol Pd.
3.4 Comparison of palladacycles with Pd(OAc)2:
Table 4. Comparison of palladacycles with Pd(OAc)2.
Entry
Cat.
BZa
(%)
TONc
(×108)
1
2
3
4
5b
Pd(OAc)2
1
2
3
1
9
62
54
52
60
0.4
3.1
2.7
2.6
3.0
TOF
(×107)
(h−1)
0.9
6.2
5.4
5.2
6.0
Reaction conditions: 4a (0.5 mmol), 5a (0.75 mmol), K2CO3 (1.5 mmol), [Pd] (10−7 mol%), CO (2 bar), anisole (11 mL) at
140 °C for 5 h. a GC yield (calculated as an average of triplicate measurements). b Scale up: 4a (5 mmol), 5a (7.5 mmol),
K2CO3 (15 mmol), [Pd] (10−7 mol%), CO (2 bar), anisole (20 mL) at 140 °C for 5 h. c mol product per mol Pd.
BZ‒Benzophenone.
4. Conclusions:
In conclusion, we have established the first palladacycle catalyzed carbonylative Suzuki‒Miyaura coupling of aryl iodides using
gaseous CO under thermal conditions for the synthesis of biaryl ketones. These palladacycles behave as robust catalysts and
have been used to bring out high TON’s and TOF’s. Comparison with a conventional palladium source shows their superiority
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SusChemE 2015
International Conference on Sustainable Chemistry & Engineering
October 8-9, 2015, Hotel Lalit, Mumbai
in generating the same. Relative comparison of the palladacycles shows that they exhibit almost similar catalytic activity at
concentrations as low as 10−7 mol%, with the dinorbornyl complex exhibiting a slightly better activity.
References
[1] T. Ishiyama, H. Kizaki, T. Hayashi, A. Suzuki, N. Miyaura, Palladium-Catalyzed Carbonylative Cross-Coupling Reaction of
Arylboronic Acids with Aryl Electrophiles: Synthesis of Biaryl Ketones, J. Org. Chem. 63 (1998) 4726-4731.
[2] J.–J. Brunet, R. Chauvin, Synthesis of diarylketones through carbonylative coupling, Chem. Soc. Rev. 24 (1995) 89‒95
[3] I.P. Beletskaya, A.V. Cheprakov, Palladacycles in catalysis – a critical survey, J. Organomet. Chem. 689 (2004) 4055‒4082.
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