Xin
Zhou‡
a,
Zhaozhan
Wang‡
bc,
Bo
Yu
acd,
Shaoping
Kuang
b,
Wei
Sun
e and
Yong
Yang
*acd
aCAS Key laboratory of Bio-based Materials, Qingdao Institute of Bioenergy and Bioprocess Technology (QIBEBT), Chinese Academy of Sciences, Qingdao 266101, China. E-mail: yangyong@qibebt.ac.cn
bCollege of Environment and Safety Engineering, Qingdao University of Science and Technology, Qingdao 266001, China
cShandong Energy Institute, Qingdao 266101, China
dQingdao New Energy Shandong Laboratory, Qingdao 266101, China
eState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, China
First published on 8th April 2022
Highly efficient and regioselective synthesis of amides from simple starting materials remains a great challenge. Herein, we reported a highly efficient hydroaminocarbonylation of alkenes and alkynes with amines and CO gas catalyzed by a soluble heterogeneous Pd catalyst (Pd@PPOC), in which ultrafine Pd nanoparticles (NPs) were homogeneously dispersed in a well-defined and discrete triphenyl phosphine-built-in porous organic cage (PPOC). The catalyst Pd@PPOC exhibited superior catalytic activity and excellent regioselectivity to Markovnikov adducts, outperforming those previous state-of-the-art Pd catalysts. A diverse set of branched amides and α,β-unsaturated amides were synthesized in high yields, and with broad substrate scopes spanning a range of functional groups that were well tolerated in this synthetic protocol. Remarkably, the soluble catalyst Pd@PPOC demonstrated high stability and could be easily separated and reused up to 10 times with maintenance of the catalytic performance and original structural nature. This study not only provides an efficient and sustainable synthetic method for accessing amides, but also highlights the potential of the MNPs encapsulated in the functional POCs for regioselective catalysis.
The encapsulation of metal nanoparticles (MNPs) within porous hosts, such as zeolites, metal–organic frameworks (MOFs), covalent organic frameworks (COFs), and dendrimers, represents one of the most significant advances in the field of catalysis and materials sciences.17 However, it still remains a challenge to prepare an encapsulated ultrafine MNP catalyst by simultaneously maintaining superior activity and strong stability and durability.18 In this context, several studies have shown that well-defined and discrete three-dimensional (3D) porous organic cages (POCs) with guest accessible cavities, as a new type of functional molecular open framework,19 could serve as ideal hosts for the size-controlled synthesis of ultrafine MNPs (e.g., Au, Rh, Pd, Pt, etc.) (smaller than 3 nm in size) with high stability by taking full advantage of their confined cage environment and incorporated heteroatoms (N, S, and P) inside the cavity as binding and nucleation sites.20–25 More importantly, POCs have excellent solubility with a well-maintained prefabricated skeleton in certain organic solvents, and thereby could homogenize the heterogeneous ultrafine MNPs to form soluble and stable MNPs with high dispersibility in solution, which could be hardly realized for those insoluble porous hosts.21a,b,22,24b,c,25 As a result, the reactants could rapidly and easily access the encapsulated active MNP sites in the cage as in homogeneous catalysis, thus achieving enhanced catalytic activity and selectivity. In a recent study, we successfully developed a bench-stable triphenyl phosphine-built-in porous organic cage (PPOC) with a large surface area (256 m2 g−1) and hierarchical micro- and mesopores through dynamic imine chemistry, which greatly broadens the functionalities of POCs.26 As a unique porous material, it allows the precisely controlled synthesis of well-dispersed and ultrafine PdNPs with a narrow size distribution (1.7 ± 0.3 nm), labeled as Pd@PPOC, which exhibited superior catalytic activity in a spectrum of cross-coupling reactions of aryl halides due to the positive electronic interaction between ultrafine PdNPs and functional phosphine in the cavities.
Entry | Deviation from standard conditions | NMR yield of 3ab (%) | 3a/4ac |
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1 | None | 98 (96)d | 77 |
2 | 0.4 mol% Pd@PPOC instead | 81 | 74 |
3 | Pd(PPh3)2Cl2 instead | 91 | 47 |
4 | Pd(PPh3)4 instead | 75 | 24 |
5 | Pd(OAc)2 plus PPh3 instead | 92 | 15 |
6 | Pd(NO3)2 plus PPh3 instead | 88 | 29 |
7 | Pd(TFA)2 plus PPh3 instead | 90 | 40 |
8 | PdCl2 plus PPh3 instead | 38 | 23 |
9 | Pd@CC2 instead | 8 | 17 |
10 | Pd@CC3 instead | 4 | 12 |
11 | Pd/C instead | 0 | — |
12 | Pd@PVP instead | 0 | — |
Under the optimized reaction conditions, we employed other commercially available homogeneous Pd catalysts for the reaction, including Pd(PPh3)2Cl2, Pd(PPh3)4, and different Pd salts (e.g., Pd(OAc)2, Pd(NO3)2, Pd(TFA)2 (TFA = trifluoroacetate), and PdCl2) combined with PPh3 as the ligand and maintaining a PPh3/Pd molar ratio of 2 (entries 3–8). It turns out that none of them gave better catalytic activity and regioselectivity than Pd@PPOC. Such an observation shows that the soluble Pd@PPOC with high dispersibility in solution not only outperforms those homogeneous Pd counterparts in catalytic activity but also considerably enhances the regioselectivity to the Markovnikov adduct. This might be ascribable to the electronic effect and confinement of PdNPs in the discrete and well-defined open cavities of PPOC.
To demonstrate the unique advantage of the phosphine-containing POC, we employed two soluble vicinal diamine-containing POCs (CC2 and CC3)19a,23a as the support to encapsulate PdNPs (Schemes S1 and S2, see the details in the ESI†). The resultant catalysts Pd@CC2 and Pd@CC3 with a roughly equal PdNP size (1.9 and 2.1 nm) showed poor reactivity and regioselectivity than Pd@PPOC under otherwise identical conditions, respectively (entries 9 and 10). This finding strongly indicates the critical role of phosphine implanted into the cavity of POC for boosting the catalytic activity and regioselectivity, which is also consistent with our previous results in Pd-catalyzed cross-couplings of aryl halides with the assistance of phosphine ligands.26 In addition, the commercially available heterogeneous Pd/C and the conventional surfactant polyvinylpyrrolidone (PVP) protected PdNPs (Pd@PVP) showed no reactivity (entries 11 and 12), further supporting the necessity of phosphine ligands for achieving superior activity and excellent regioselectivity in the reaction.
We subsequently investigated the stability and recyclability of the catalyst Pd@PPOC using the benchmark reaction under the optimized conditions. After completion of each run, the catalyst was successfully recovered from the reaction solution by centrifugation, washed with water and ethanol, dried at 50 °C for 4 h, and then used in a fresh reaction. As shown in Fig. 1, the catalyst Pd@PPOC could be recovered and recycled for up to 10 times without distinct loss of both activity and regioselectivity, indicating excellent stability and durability. The loading of palladium in Pd@PPOC was determined to be 14.7 wt% after 10 cycles by inductively coupled plasma optical emission spectrometry (ICP-OES), which is very close to the fresh one (15.0 wt%). HR-TEM images (Fig. S2†) for the used catalyst Pd@PPOC show no aggregation in the PdNP size with maintenance of high dispersion as the fresh one, further demonstrating that it has high stability during the catalytic reaction.
After identifying the optimized reaction conditions, we then explored the scope and limitations of this Pd-catalyzed hydroaminocarbonylation of alkenes for the synthesis of various amides (Table 2). Firstly, the scope of anilines was investigated. A variety of anilines incorporated with electron-neutral, electron-donating, and electron-withdrawing substituents could undergo coupling with styrene and CO to furnish the desired amides in high yields with excellent regioselectivity (3a–3l). ortho-Substituted anilines were also compatible with the present conditions and showed no obvious difference in the catalytic performance compared with meta- and para-substituted anilines (2b, 2e, and 2f), implying a negligible steric effect. Anilines with halide substituents, such as –F (2h), –Cl (2i), and –Br (2j), and strong electron-withdrawing groups, such as –CF3 (2k) and –CONH2 (2l), were tolerable in the reaction to deliver the corresponding amides in a slightly lower yield albeit with excellent regioselectivity. The reaction of styrene with quinolin-8-amine (2m) and CO also proceeded well, regioselectively furnishing the corresponding amide 3m in 85% yield. Pleasingly, the more challenging aliphatic amine (benzylamine 2n) and secondary amine (morpholine 2o) also underwent Markovnikov hydroaminocarbonylation smoothly to afford the corresponding amides in 53 and 72% yields with high regioselectivity, respectively.
a Reaction conditions: alkene (0.5 mmol), amine (0.6 mmol), HCl (0.6 mmol), Pd@PPOC (0.8 mol% Pd), CO (4.0 MPa), NMP (3.0 mL), 110 °C, 12 h. The ratios of branched/linear amide were determined by GC-MS analysis of the crude products. b 24 h. c Aniline (1.2 mmol), HCl (1.2 mmol). Isolated yields are reported. |
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Secondly, the scope of alkenes was examined. A spectrum of styrenes bearing electron-donating and electron-withdrawing substituents at the ortho-, meta-, and para-positions of the phenyl ring could couple with aniline and CO to furnish the corresponding Markovnikov amides (3p–3ab) in high yields with excellent regioselectivity (overall higher than 69). No obvious steric or electronic effect was observed in all investigated styrenes. Heteroaryl alkene, i.e., 1-tosyl-3-vinyl-1H-pyrrole 1ac, also underwent the reaction very well to deliver the desired amide 3ac in 88% yield with excellent regioselectivity. Remarkably, the challenging aliphatic alkenes, including norbornene (1ad), bicyclo[2.2.1]hepta-2,5-diene (1ae), and ethyl acrylate (1af), were also tolerated in the reaction to give the desired amides in moderate to good yields (3ad–3af, 47–77%). To demonstrate the utility of this Pd-catalyzed hydroaminocarbonylation, pharmaceutically related derivatives, i.e., ibuprofen (3ag) and ketoprofen (3ah), and biologically active natural derivatives containing a CC bond, i.e., pregnenolone (1ai) and testosterone (1aj), could be smoothly hydroaminocarbonylated into their respective amides in good to high yields with excellent regioselectivity. In addition, this synthetic protocol could be easily scaled up and the gram-scale synthesis of 3a was successful with maintenance of the activity and regioselectivity under the optimal conditions (Scheme S3†), highlighting its practical potential.
Given the generality of the substrate scope and superior catalytic performance in the Markovnikov hydroaminocarbonylation of alkenes, we next turned our attention to explore terminal alkynes as starting materials for accessing α,β-unsaturated amides. We conducted the reactions using the same conditions as those for hydroaminocarbonylation of alkenes, and the results are presented in Table 3. In general, a diverse set of terminal alkynes smoothly underwent the Markovnikov hydroaminocarbonylation with various anilines and CO pressures to deliver functionalized acrylamides in good to high yields with high Markovnikov regioselectivity. Firstly, phenylacetylenes with substituted groups at the ortho-, meta-, and para-positions of the phenyl ring (5a–5l) coupled with aniline and CO very well, affording their respective α,β-unsaturated amides (6a–6l) in high yields with Markovnikov to anti-Markovnikov regioselectivities varying from 13 to 37. Impressively, halogen-substituted phenylacetylenes (5g–5l) were compatible with the present conditions to deliver their corresponding acrylamides, which allows for their late-stage functionalization to construct more structurally complex and useful compounds via cross-coupling reactions. Secondly, a set of anilines featuring various substituents were examined. Anilines containing electron-donating and electron-withdrawing groups, such as –Me, –OMe, –F, –Cl, –Br, –CN, –CF3, and –CONH2, were well tolerated under the present conditions to give the desired α,β-unsaturated amides (6m–6y) in high yields with excellent regioselectivity.
Our previous study has clearly indicated that the ultrafine Pd NPs confined in PPOC has a strong interaction with PPh3 in the skeleton with the formation of Pd–P coordination bonds,26 which makes this soluble heterogeneous Pd catalyst just like homogeneous phosphine-ligated Pd complexes. According to the above results and previous mechanistic investigation on the Pd-catalyzed hydroaminocarbonylation,3,5–8 we propose that the reaction proceeds via the following pathways as shown in Scheme 2. First, the active [Pd–H] species A is formed in situ from the reaction of Pd@PPOC and HCl, which is similar to the homogeneous system.5 Then, insertion of alkene into [Pd–H] species A affords the alkyl-Pd intermediates B and B′. The alkyl-Pd B and B′ undergo CO insertion to give the corresponding acyl-Pd intermediates C and C′, respectively. Complexes D and D′ are formed through amine insertion, which undergo reductive elimination leading to amides and regenerate the palladium hydride species.
Footnotes |
† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d2gc00815g |
‡ These authors contributed equally to this work. |
This journal is © The Royal Society of Chemistry 2022 |