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In Situ Generation of Palladium Nanoparticles: Ligand-Free Palladium Catalyzed Pivalic Acid Assisted Carbonylative Suzuki Reactions at Ambient Conditions Qing Zhou,† Shaohua Wei,†,‡ and Wei Han*,†,‡ †
Jiangsu Key Laboratory of Biofunctional Materials, Key Laboratory of Applied Photochemistry, School of Chemistry and Materials Science, Nanjing Normal University, Wenyuan Road No. 1, Nanjing 210023, China ‡ Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Nanjing 210023, China S Supporting Information *
ABSTRACT: Highly selective carbonylative Suzuki reactions of aryl iodides with arylboronic acids using an in situ generated nanopalladium system furnished products in high yields. The reactions were performed under ambient conditions and in the absence of an added ligand. The key to success is the addition of pivalic acid, which can effectively suppress undesired Suzuki coupling. The synthesis can be easily scaled up, and the catalytic system can be reused up to nine times. The nature of the active catalytic species are discussed.
P
nanoparticles.5i,8 In addition, under mild conditions or even at room temperature the in situ nanocatalytic systems can achieve efficient catalysis.7 Herein we report the first examples of an efficient nanopalladium catalytic system for carbonylative Suzuki reactions of aryl iodides without an additional ligand. Remarkably, this transformation proceeds smoothly at ambient temperature and pressure, which has also never been reported so far. In our previous work, the in situ generated palladium nanoparticles effectively catalyzed the Suzuki coupling reactions of aryl chlorides with arylboronic acids at room temperature in PEG-4009 (poly(ethylene glycol) with an average molecular weight of 400 Da).7c This work implies that the suppression of undesired Suzuki coupling reactions will be a daunting challenge when in situ generated palladium nanoparticles are used to catalyze carbonylative Suzuki reactions in PEG-400. It is well-known that a base plays an important role in palladiumcatalyzed cross-coupling reactions. Hence, we initially investigated the effect of various bases on the model carbonylative Suzuki reaction of 4-iodonitrobenzene with phenylboronic acid at ambient temperature and pressure in PEG-400 (Table 1). The bases such as K2CO3, Cs2CO3, Na2CO3, KF, and TBAF· 2H2O resulted in a significant amount of Suzuki coupling product 3a′a′ (Table 1, entries 1−5), whereas K3PO4 afforded desired carbonylative product 3aa in a good yield, albeit with the concomitant generation of 3a′a′ in 13% yield (Table 1, entry 7). Recently, Han and co-workers reported that pivalic acid can effectively suppress Suzuki reactions.10 We assumed that the
alladium-catalyzed carbonylative Suzuki reactions of aryl-X compounds with the C1 building block carbon monoxide are becoming a valuable tool in the synthesis of biaryl ketones that are important moieties in numerous natural products, pharmaceuticals, photosensitizers, and advanced organic materials.1 Over the past decade, there have been great advances in the substrate scope, functional group tolerance, and range of various catalysts for promoting the transformation.2 However, the vast majority of these methods require elevated temperatures (≥80 °C) and/or relatively high pressure (≥5 bar). Moreover, the cost of ligands are almost always necessary to achieve efficient catalysis.2 All of these drawbacks impede the transfer of the advances to large-scale applications, particularly in complex organic syntheses. As carbon monoxide is relatively inert (bond energy, 257 kcal/mol) and can deactivate palladium,3 the development of general room-temperature carbonylative Suzuki reactions of aryl-X compounds with arylboronic acids and carbon monoxide that proceed under atmospheric pressure without an extra ligand remains an important challenge for organic synthetic chemists. Palladium nanoparticles usually show enhanced reactivity under mild conditions due to their large surface area4 and have been widely used as catalysts in carbon−carbon bond-formation reactions.5 Nevertheless, to the best of our knowledge, their applications as catalysts for carbonylative Suzuki reactions have not yet been reported.6 This may be because palladium nanoparticles are known as excellent catalysts for Suzuki couplings5d,e and will contribute to problem of chemoselectivity when they are used for carbonylative Suzuki reactions. We recently developed in situ generated metal nanoparticlescatalyzed cross-coupling reactions.7 One of the attractive features of the in situ generated nanometal systems is to circumvent cumbersome processes for the preparation of metal © XXXX American Chemical Society
Received: October 25, 2013
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dx.doi.org/10.1021/jo402366p | J. Org. Chem. XXXX, XXX, XXX−XXX
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Table 1. Pd(OAc)2-Catalyzed Carbonylative Suzuki Reaction of 1a with 2aa
entry
base
time (h)
yield of 3aa (%)
yield of 3a′a′ (%)
1 2 3 4 5 6 7 8c 9b,c 10b,c,d 11b,c 12b,c
K2CO3 Cs2CO3 Na2CO3 KF TBAF·2H2O NH3·H2O K3PO4 K3PO4, tBuCO2H K3PO4, tBuCO2H K3PO4, tBuCO2H K3PO4, CH3CO2H K3PO4, CF3CO2H
1 1 3 4 9 9 1 2 3 4 3 3
44 31 59 50 30 trace 83 84 90 85 51 74
46 61 32 36 31 trace 13 10 5 5 8 5
Scheme 1. Carbonylative Suzuki Reactions of Aryl Halides with 2a at Ambient Temperature and Pressure
a
Reaction conditions (unless otherwise noted): 1a (0.5 mmol), 2a (0.75 mmol), CO (balloon), base (1.0 mmol), Pd(OAc)2 (2 mol %), PEG-400 (2.0 g), rt. bWith K3PO4 (0.75 mmol) for entries 9−12. c With acid (0.25 mmol) for entries 8−12. dThe same conditions as above except with 1 mol % Pd(OAc)2.
methyl ester, and nitro on the aryl ring were well tolerated under the optimized reaction conditions. 1-Iodonaphthalene was found to be a good substrate for the transformation to furnish carbonylative product 3na in 85% yield. Moreover, 2iodothiophene as an example of a heterocyclic iodide gave 87% yield of desired coupling product 3oa. Unfortunately, 4bromonitrobenzene was unreactive. However, our previous report indicated that this catalytic system was efficient for the Suzuki reactions using aryl chlorides and bromides as substrates.7c,d To explain this observation, the control experiments were conducted: Suzuki reaction was completely inhibited (the desired product was not observed in 20 h) when the catalytic system of the previous report7c was performed in carbon monoxide atmosphere (ambient pressure), whereas this Suzuki reaction became quite slow (59% yield after1 h) when the pivalic acid was added to the original catalytic system (Scheme 2). These experiments suggest that the carbon monoxide plays a decisive role in deactivating or poisoning palladium catalyst.
addition of the pivalic acid could suppress the formation of Suzuki coupling product in our case and may favor of the insertion of carbon monoxide from the gas phase. Gratifyingly, K3PO4/tBuCO2H as the base achieved an excellent yield of 3aa in 90% with only 5% yield of the side product 3a′a′ at ambient temperature and pressure (Table 1, entry 9).10 Other carboxylic acids such as CH3COOH and CF3COOH were tested (Table 1, entries 11 and 12). Although they also suppressed the Suzuki reaction, they gave lower yields of 3aa under otherwise identical conditions. Furthermore, the role of the tBuCO2H to suppress the Suzuki coupling reaction and favor the carbonylative Suzuki coupling reaction was underlined by control experiments (Table 2). Table 2. Effect of tBuCO2H on Products of the Reaction of 1-Iodo-3,5-dimethylbenzene (1b) with 2aa
Scheme 2. Effect of Various Conditions on the Suzuki Reaction of 4-Chloronitrobenzene and Phenylboronic Acid entry 1 2
tBuCO2H
time (h)
yield of 3ba (%)
yield of 3b′a′ (%)
tBuCO2H
6 48
48 94
50 trace
a
Reaction conditions (unless otherwise stated): 1b (0.5 mmol), 2a (0.75 mmol), CO (balloon), K3PO4 (0.75 mmol), tBuCO2H (0.25 mmol), Pd(OAc)2 (2 mol %), PEG-400 (2.0 g), rt.
We next examined various aryl halides to couple with phenylboronic acid (2a) and CO (ambient pressure) by using K3PO4/tBuCO2H as the base and Pd(OAc)2 as the catalyst in PEG-400 at room temperature (Scheme 1). The reactions worked smoothly with aryl iodides having ortho-, meta-, and para-substituents on the aryl ring to afford desired products 3aa−3oa in 85−96% yields. A variety of functional groups such as methyl, trifluoromethyl, trifluoromethoxy, chloro, fluoro,
Interestingly, double carbonylation of diiodobenzenes, including 1,2-diiodobenzene (1q), 1,3-diiodobenzene (1r), and 1,4-diiodobenzene (1s), provided diketones in 85%, 80%, and 95% yields, respectively (Scheme 3). The diketones are key intermediates for advanced functional materials.1b,d Subsequently, the scope of the catalytic system for various arylboronic acids was evaluated (Scheme 4). Arylboronic acids B
dx.doi.org/10.1021/jo402366p | J. Org. Chem. XXXX, XXX, XXX−XXX
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reaction smoothly and gave carbonylative Suzuki products up to 92% yield (i.e., 3ab, 3ae, 3ak, 3ck, 3ek, and 3ok). To our delight, a heterocyclic boronic acid, 2-thiopheneboronic acid (2o), was successfully transformed to desire product in a good yield (3ao) with a lower catalyst loading. Additionally, 4,4′difluorobenzophenone (3jq), a key intermediate in the synthesis of denagliptin used for the treatment of type II diabetes, was produced in 90% yield under the applied reaction conditions.11 However, 2,6-dimethylphenylboronic acid, 4pyridinylboronic acid, and potassium phenyltrifluoroborate were found to be ineffective educts. Encouraged by the results presented above, we subsequently carried out a carbonylative Suzuki reaction on a gram scale to demonstrate its utility. With 5 mmol of 1a, 3aa was produced in 85% yield under normal conditions (Scheme 5). Furthermore,
Scheme 3. Double Carbonylative Suzuki Reactions of Diiodobenzenes
Scheme 5. Gram-Scale Synthesis of 3aa
the recyclability of the catalytic system was tested for the model reaction of 4-iodonitrobenzene with phenylboronic acid and carbon monoxide. The catalytic system maintained its high selectivity for nine consecutive cycles (Figure 1). After the nine-
Scheme 4. Carbonylative Suzuki Reactions of Arylboronic Acids with Aryl Iodides at Ambient Temperature and Pressure
Figure 1. Catalyst reusability study.
run recycling uses, the total leaching of Pd to the combined diethyl ether extracts was found to be 4.2% (percentage of the Pd placed in the reaction) by ICP analysis. In order to ascertain the real working catalyst, transmission electron microscopy (TEM) was used to examine the sample collected from the mixture of the model reaction under the standard conditions. The TEM result revealed palladium nanoparticles in situ generated and dispersed well in PEG400 with an average particle size of 2.6 nm (Figure 2), consistent with our previous reports.7 Additionally, ex situ generated palladium nanoparticles were prepared in PEG-400 according to our previously described method7c and then directly utilized to catalyze the model reaction under the standard conditions to furnish product 3aa in 83%, comparable to the yield using the in situ generated palladium nanoparticles. Although the in situ generated palladium nanoparticles showed good activity, we still did not know whether the catalysis occurred on the cluster surface or by leached Pd species.5g,12 Hence, control experiments were conducted to assess the homo/heterogeneous nature of the active nanocatalyst. A large excess of Hg(0) (relative to palladium) was added to the model
having either electron-donating or electron-withdrawing substituents worked well and delivered expected products in good to excellent yields. Remarkably, sensitive functional groups, such as hydroxyl, chloro, bromo, and nitrile, were well tolerated (i.e., 3af, 3ak, 3ck, 3ek, 3ok, 3al, and 3am). Sterically hindered arylboronic acids also underwent the C
dx.doi.org/10.1021/jo402366p | J. Org. Chem. XXXX, XXX, XXX−XXX
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studies suggest a typical heterogeneous reaction process is unlikely to be in operation.
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General Procedure A: Preparation of (4-Nitrophenyl)(phenyl)methanone. A 25-mL flask was charged with 4-iodonitrobenzene (0.5 mmol, 127.0 mg), phenylboronic acid (0.75 mmol, 92.4 mg), palladium acetate (0.01 mmol, 2.4 mg), K3PO4 (0.75 mmol, 164.2 mg), tBuCO2H (0.25 mmol, 25.8 mg), and PEG-400 (2.0 g) before standard cycles of evacuation and backfilling with dry and pure carbon monoxide. The mixture was stirred under ambient temperature and pressure for the indicated time. At the end of the reaction, the reaction mixture was extracted with diethyl ether (3 × 15 mL). The organic phases were combined, and the volatile components were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether/diethyl ether = 25:1). In the recycling experiment, the residue was subjected to a second run by charging it with the same substrates as mentioned above without further addition of Pd(OAc)2 and PEG 400. In the third, sixth, and eighth runs, another 0.5 mL of PEG-400 was added to the reaction mixture. General Procedure B: Preparation of 1,2-Phenylenebis(phenylmethanone). A 25-mL flask was charged with 1,2diiodobenzene (0.5 mmol, 171.2 mg), phenylboronic acid (1.5 mmol, 184.8 mg), palladium acetate (0.01 mmol, 2.4 mg), K3PO4 (1.5 mmol, 328.4 mg), tBuCO2H (0.5 mmol, 51.6 mg), and PEG-400 (2.0 g) before standard cycles of evacuation and backfilling with dry and pure carbon monoxide. The mixture was stirred under ambient temperature and pressure for the indicated time. At the end of the reaction, the reaction mixture was extracted with diethyl ether (3 × 15 mL). The organic phases were combined, and the volatile components were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether/ ethyl acetate/triethylamine = 25:1:0.1). (4-Nitrophenyl)(phenyl)methanone (3aa).14 Following general procedure A, 3aa was isolated as a light pink solid (102 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 2 H), 7.92 (d, J = 8.8 Hz, 2 H), 7.79−7.77 (m, 2 H), 7.64 (tt, J = 7.4 Hz, J = 1.3 Hz, 1 H), 7.51 ppm (t, J = 7.7 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 194.8, 149.8, 142.9, 136.3, 133.5, 130.7, 130.1, 128.7, 123.5 ppm; mp 136.8− 137.2 °C. 3,5-Dimethylphenyl)(phenyl)methanone (3ba).14 Following general procedure A, 3ba was isolated as a light yellow solid (99 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 7.80−7.77 (m, 2 H), 7.56 (tt, J = 7.4 Hz, J = 1.3 Hz, 1 H), 7.46 (t, J = 7.8 Hz, 2 H), 7.38 (s, 2 H), 7.20 (s, 1 H), 2.36 ppm (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 197.1, 137.88, 137.86, 137.7, 134.0, 132.2, 130.0, 128.2, 127.8, 21.20 ppm; mp 58.4−59.3 °C. Phenyl(p-tolyl)methanone (3ca).14 Following general procedure A, 3ca was isolated as a white solid with low melting point (84 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 7.78−7.75 (m, 2 H), 7.71 (d, J = 8.0 Hz, 2 H), 7.56 (tt, J = 7.4 Hz, J = 1.3 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 2.42 ppm (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 196.5, 143.2, 137.9, 134.8, 132.1, 130.3, 129.9, 129.0, 128.2, 21.6 ppm. Phenyl(m-tolyl)methanone (3da).14 Following general procedure A, 3da was isolated as light yellow oil (83 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.80−7.77 (m, 2H), 7.61 (s, 1 H), 7.60−7.54 (m, 2 H), 7.46 (m, 2 H), 7.39−7.32 (m, 2 H), 2.40 ppm (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 197.0, 138.1, 137.7, 137.6, 133.2, 132.3, 130.4, 130.0, 128.2, 128.1, 127.4, 21.4 ppm. Phenyl(o-tolyl)methanone (3ea).14 Following general procedure A, 3ea was isolated as a light yellow oil (88 mg, 90%). 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 7.80−7.77 (m, 2 H), 7.56 (tt, J = 7.4 Hz, J = 1.3 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.38 (td, J = 7.4 Hz, J = 1.6 Hz, 1 H), 7.31−7.21 (m, 3 H), 2.31 ppm (s, 3 H); 13 C NMR (100 MHz, CDCl3) δ 198.7, 138.6, 137.7, 136.7, 133.1, 131.0, 130.2, 130.1, 128.5, 128.4, 125.2, 20.0 ppm.
Figure 2. TEM image of the in situ generated palladium nanoparticles (scale bar = 20 nm).
reaction under the standard conditions and had no significant effect on the catalytic activity (eq 1). Furthermore, the
introduction of quantitative CS2 evaluated the presence of a homo/heterogeneous catalyst (Table 3). When 0.65 equiv of Table 3. Quantitative CS2 Poisoning Experiments
entry
CS2 (equiv)
time (h)
yield (%)
1 2 3 4
0 0.65 1.0 1.5
3 3 3 3
90 85
