Palladium-catalyzed hydrocarbonylative cross-coupling with two different alkenes

Abstract

Transition metal-catalyzed hydrocarbonylation of alkenes has been widely studied; however, the hydrocarbonylation reaction that took place between two alkenes has been largely unexplored. Herein, we report a palladium-catalyzed hydrocarbonylative cross-coupling reaction with two different alkenes to produce structurally diverse β-ketoaldehyde surrogates, which can be easily converted to different types of heterocycles including pyrazole, isoxazole and pyrimidine.

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Transition metal-catalyzed hydrocarbonylation of alkenes is one of the most prominent methods for synthesizing carbonylated compounds. This process is widely used in the industrial production of fine chemicals and in the synthesis of natural products and bioactive molecules.¹ Since Reppe's seminal work in the last century,² transition metal-catalyzed hydrocarbonylation reactions using different types of nucleophiles to trap acylmetal species have been extensively studied, providing efficient and rapid synthesis of value-added amides, imides, carboxylic acids, esters, and thioesters.^1,3 Despite the power and scope of these tremendous advances, most of the known methods focus on the hydrocarbonylation of a single alkene and the construction of C–O, C–N and C–S bonds. Only a few types of hydrocarbonylation reactions have been developed to form C–C bonds.⁴ Given the robustness of cross-coupling reactions with different alkenes in constructing C–C bonds and building molecular complexity,⁵ the hydrocarbonylative cross-coupling reaction with two different alkenes to form C–C bonds is thus of considerable interest. There are two studies involving this type of cross-coupling reaction,^4b,c but both of them focused on the formation of linear carbonyl compounds and the use of aromatic alkenes as coupling partners.

Recently, we have developed a new and efficient strategy for the carbonylative assembly of two different alkenes, initiated by palladium-catalyzed hydrocarbonylative cycloadditions.^6,7 These reactions provided novel strategies to furnish bridged carbonylated polycyclic molecules from two different alkenes in the presence of CO. Remarkable chemoselectivity was achieved by using the directing effect of the aldehyde or ketone functionality attached to one of the alkenes (Scheme 1A). Inspired by these results and in line with our continuing interest in carbonylation chemistry,^1d,3i,j,8 we envisioned that the hydrocarbonylative cross-coupling reactions might also be realized between two alkenes with opposite electronic properties. Specifically, electron-deficient alkenes tend to be hydrocarbonylated to generate the corresponding acylmetal species under suitable conditions. Meanwhile, electron-rich alkenes, such as alkenyl ethers and alkenyl amines, could act as nucleophiles to capture the acylmetal species to furnish the carbonylative coupling products. Herein, we describe the development of a palladium-catalyzed chemoselective hydrocarbonylative cross-coupling reaction between electron-rich and electron-deficient alkenes in the presence of CO (Scheme 1B). Using this strategy, a wide range of β-ketoaldehyde surrogates were obtained, which are not only common structural motifs in bioactive compounds and natural products, such as tandyukisin, lymphostin and australifungin,⁹ but are also known as attractive building blocks in organic synthesis.¹⁰ Furthermore, a series of heterocycles were synthesized from the carbonylated products, which further demonstrated the applicability of this reaction.

Scheme 1 Hydrocarbonylative cross-coupling with two different alkenes.

We started our investigations with 3,4-dihydro-2H-pyran (1a) and acrylonitrile (2a) as substrates in anisole at 100 °C using Ruphos as a ligand to test different palladium catalyst precursors. To our delight, the desired product 3a could be easily obtained in 87% isolated yield when Pd(CH₃CN)₂Cl₂ was utilized as the catalyst (Table 1, entry 1). PdBr₂ and PdI₂ showed lower catalytic activity, while other catalysts such as Pd(OAc)₂ and Pd(acac)₂ were ineffective for this carbonylation reaction (Table 1, entries 2–5). Subsequently, several ligands were evaluated (Table 1, entries 6–9), with Sphos and Davephos exhibiting comparable outcomes in this reaction, providing the desired products in 84% and 81% yields, respectively. Moreover, several common solvents such as THF, toluene, PhOMe and PhCl were also assessed (Table 1, entries 10–13); however, they afforded the products in lower yields.

Table 1 Optimization of the reaction conditions^a

Entry	[Pd]	Ligand	Solvent	Yield (%)
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), catalyst (0.025 mmol, 5 mol%), ligand (0.06 mmol, 12 mol%), L-CSA (L-camphorsulfonic acid, 0.025 mmol, 5 mol%), CO (40 atm), solvent (1.0 mL), 100 °C, 12 hours, isolated yield. b Xantphos (0.03 mmol, 6 mol%).
1	Pd(CH3CN)2Cl2	Ruphos	NMP	87
2	PdBr2	Ruphos	NMP	61
3	PdI2	Ruphos	NMP	23
4	Pd(OAc)2	Ruphos	NMP	Trace
5	Pd(acac)2	Ruphos	NMP	Trace
6	Pd(CH3CN)2Cl2	Sphos	NMP	84
7	Pd(CH3CN)2Cl2	Davephos	NMP	81
8	Pd(CH3CN)2Cl2	^nBuPAd2	NMP	63
9	Pd(CH3CN)2Cl2	Xantphos^b	NMP	21
10	Pd(CH3CN)2Cl2	Ruphos	THF	15
11	Pd(CH3CN)2Cl2	Ruphos	Toluene	Trace
12	Pd(CH3CN)2Cl2	Ruphos	PhOMe	25
13	Pd(CH3CN)2Cl2	Ruphos	PhCl	13

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With the optimized reaction conditions established, the scope of this hydrocarbonylation process with respect to the electron-rich alkenes was first investigated (Scheme 2). As expected, 2,3-dihydrofuran was also an effective substrate for this reaction, affording the corresponding product (3b) in 66% yield. Notably, substrates containing acid-sensitive acetal functionality survived in this reaction, although product 3c was obtained in a lower yield. A variety of enol ethers bearing various substituents such as tetrahydro-2H-pyranyl, piperidyl, cyclohexyl and benzyl groups were all converted smoothly to the corresponding β-ketoaldehyde surrogates (3d–3g) in moderate to good yields. Moreover, enamides were also suitable substrates and reacted efficiently to deliver products 3h–3j. In addition to these medicinally important motifs, the chloro group, as well as ester and phthalimide functionalities, in products 3k–3m could provide a useful handle for further elaboration. It is worth noting that the reaction showed excellent chemoselectivity when enol ethers containing another alkenyl group were used as the substrates. The corresponding β-ketoaldehyde surrogates 3n–3p were smoothly formed, leaving another C=C bond behind. This good chemoselectivity may arise from the higher nucleophilicity of enol ethers. Furthermore, to demonstrate the potential of this hydrocarbonylation process in the diversification of natural products, a variety of enol ethers derived from citronellal, Lily aldehyde and cyclamen aldehyde were exploited, providing the desired products in moderate yields (3n and 3q–3r). We then turned our attention to vinyl ethers, and this electron-rich alkene afforded the desired mono-protected β-ketoaldehyde (3s) with a slightly reduced yield. Next, we investigated the generality of this hydrocarbonylation of alkenes. Unfortunately, only a few electron-deficient alkenes could be employed in this reaction (3t–3v).

Scheme 2 Substrate scopes. Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Pd(CH₃CN)₂Cl₂ (0.025 mmol, 5 mol%), Ruphos (0.06 mmol, 12 mol%), L-CSA (0.025 mmol, 5 mol%), CO (40 atm), NMP (1.0 mL), 100 °C, 12 hours. Isolated yield. The values of E/Z and dr were determined by H NMR. ^a 2 (1.5 mmol), 90 °C, 24 h. ^b 2 (1.5 mmol), 110 °C. ^c PdI₂ instead of Pd(CH₃CN)₂Cl₂. ^d Davephos instead of Ruphos.

To demonstrate the synthetic potential of this reaction, we first conducted this carbonylation reaction on a gram scale, and the corresponding product 3g was obtained in 1.7 g with 74% yield (Scheme 3). In addition, a series of reactions were conducted to demonstrate the utility of our carbonylation reaction in achieving relevant heterocycles, which generally exhibit a diverse range of biological activities and play pivotal roles in medicinal chemistry.¹¹ As shown in Scheme 3, the corresponding N-aryl-pyrazole and pyrazole derivatives (4 and 5) were readily obtained by treating 3g with hydrazine hydrate or phenylhydrazine in HOAc with 81% and 84% yields, respectively. In addition, 3,4-disubstituted isoxazole derivative 6 could also be obtained smoothly with 64% yield starting from 3g and hydroxylamine hydrochloride. Furthermore, 2,4,5-trisubstituted pyrimidine 7 was obtained in 63% yield from 3g, benzamidine hydrochloride and NaOMe at 80 °C.

Scheme 3 Gram-scale reaction and synthetic applications.

Based on the previous reports,⁴ a tentative mechanism of this hydrocarbonylation of two alkenes to construct β-ketoaldehyde surrogates is proposed (Fig. 1). Initially, the pre-catalyst Pd(II) is reduced to Pd(0) under the reaction conditions and then an oxidative addition of Pd(0) with L-camphorsulfonic acid (L-CSA) results in the formation of a cationic [H–PdL]⁺ complex and a camphorsulfonic anion (X⁻). The hydropalladium of acrylonitrile affords the alkylpalladium species I, which further reacts with CO to give acylpalladium II. The subsequent nucleophilic substitution of II produces intermediate III and regenerates the Pd(0) species for the next catalytic cycle. The desired product 3 is then generated via the deprotonation of intermediate III with the assistance of the anion.

Fig. 1 Proposed reaction mechanism.

Conclusions

In conclusion, we have developed a novel approach for palladium-catalyzed hydrocarbonylative cross-coupling between electron-deficient alkenes and enol ethers or enamides. The reaction provides a shortcut to access a series of β-ketoaldehyde surrogates from a diverse range of electron-rich alkenes. Different types of heterocycles including pyrazole, isoxazole and pyrimidine have been prepared originating from simple enol ether, CO and acrylonitrile, demonstrating the synthetic potential of this hydrocarbonylation reaction.

Author contributions

Y. Chen, J. Wu and Y. Ding conducted the experiments. Y. Ding wrote the initial manuscript draft. H. Huang conceptualized and directed the project and finalized the manuscript draft. All authors contributed to discussions.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

We are grateful for financial support from the National Key R&D Program of China (2023YFA1507500), the National Natural Science Foundation of China (21925111, 22350008 and 22301289), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0450301). This work was partially carried out at the Instruments Center for Physical Science, University of Science and Technology of China.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4qo01312c

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