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. 2019 Sep 21;20:229–236. doi: 10.1016/j.isci.2019.09.027

Synthesis of (E,E)-Dienones and (E,E)-Dienals via Palladium-Catalyzed γ,δ-Dehydrogenation of Enones and Enals

Gao-Fei Pan 1,2, Xing-Long Zhang 1,2, Xue-Qing Zhu 1, Rui-Li Guo 1, Yong-Qiang Wang 1,3,∗
PMCID: PMC6817633  PMID: 31590075

Summary

A new strategy for the synthesis of conjugated (E,E)-dienones and (E,E)-dienals via a palladium-catalyzed aerobic γ,δ-dehydrogenation of enones and enals has been developed. The method can be employed in the direct and efficient synthesis of various (E,E)-dienones and (E,E)-dienals, including non-substituted α-, β-, and γ- and/or δ-substituted (E,E)-dienones and (E,E)-dienals. The protocol is featured by the ready accessibility and elaboration of the starting materials, good functional group compatibility, and mild reaction conditions. Furthermore, the reaction is of complete E,E-stereoselectivity and uses molecular oxygen as the sole clean oxidant.

Subject Areas: Catalysis, Organic Synthesis, Chemical Compounds in Materials Science

Graphical Abstract

graphic file with name fx1.jpg

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Highlights

  • •

    Good compatibility of various substitutions

  • •

    Complete E,E-stereoselectivity

  • •

    Ready accessibility of the starting materials

  • •

    Oxygen as the sole oxidant

Catalysis; Organic Synthesis; Chemical Compounds in Materials Science

Introduction

(E,E)-α,β,γ,δ-unsaturated carbonyl structural motifs are prevalent in natural products, drug molecules, and functional organic materials (Harned and Volp, 2011, Woerly et al., 2014). Conjugated dienones and dienals are also versatile precursors for 1,2- (Zhang and Morken, 2009), 1,4- (Csákÿ et al., 2010, Amoah and Dieter, 2017), or 1,6-addition (Poulsen et al., 2015, den Hartog et al., 2015, Caruana et al., 2014, Shaw and White, 2015, Gu et al., 2015); Diels-Alder reaction (Xiong et al., 2012, Li et al., 2012, Tian et al., 2014); cycloaddition (Horie et al., 2011, Albrecht et al., 2012); and other transformations (Meisner et al., 2012, Bos et al., 2013). Traditionally, the approaches to access conjugated dienones or dienals involve Knoevenagel condensation (He et al., 2011), Wittig-Horner reaction (An et al., 2015, Poulsen et al., 2016), Claisen rearrangement (Cookson and Gopalan, 1978, Motika et al., 2015), and addition-elimination reaction (Crouch et al., 2011, Yuan and Han, 2012, Kim and Oh, 2015, Li et al., 2019). These methods usually require basic conditions, which might be incompatible with the existing functional groups and/or the original stereochemistry. Moreover, these methods are often multistep sequences and suffer from low yields. In 1988, Trost's group (Trost and Schmidt, 1988, Trost and Kazmaier, 1992, Trost and Rudd, 2002, Trost and Rudd, 2005, Trost and Biannic, 2015) and Lu's group (Guo and Lu, 1993, Inoue and Imaizumi, 1988, Kwong et al., 2008, Lu et al., 2001, Ma et al., 1988, Ma et al., 1989) independently and virtually simultaneously developed the isomerization of alkynones to the corresponding conjugated dienones (Scheme 1A, a). Recently, Li's group reported a palladium-catalyzed isomerization of 4-alkynals to conjugated dienals (Scheme 1A, b) (Hearne and Li, 2017). In spite of the alkyne isomerization protocol being a great advance in view of the relatively mild reaction conditions, the inherent structural feature of alkyne prevents the method from the direct preparation of multi-substituted dienones and dienals. More recently, Alexanian et al. reported an elegant cobalt-catalyzed carbonylative cross-coupling of alkyl tosylates and dienes to synthesize conjugated dienones (Scheme 1A, c) (Sargent and Alexanian, 2017). Also, Huang et al. reported a great direct aerobic α,β-dehydrogenation of γ,δ-unsaturated amides and acids to produce conjugated dienamides and dienoic acids by an iridium/copper relay catalysis process (Scheme 1A, d) (Wang et al., 2018). Although these remarkable progresses have been made, significant challenges remain unaddressed, for example, limited substrate scope and tedious preparation of starting material. Therefore, new strategies for facile and efficient synthesis of conjugated dienones and dienals are still highly desirable.

Scheme 1.

Scheme 1

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Strategies for Synthesis of (E,E)-Dienones and (E,E)-Dienals

(A) Previous work for synthesis of (E,E)-dienones and (E,E)-dienals.

(B) Our work for synthesis of (E,E)-dienones and (E,E)-dienals.

(C) Reaction mechanism for the palladium-catalyzed γ,δ-dehydrogenation of enones and enals.

Our group has long sought catalytic conditions for aerobic dehydrogenation reactions. We thought if dienones or dienals could be prepared by the aerobic γ,δ-dehydrogenation of enones or enals (Scheme 1B). This strategy has two advantages: (1) the precursors, enones or enals, can be obtained readily (some of them are commercially available and they also can be easily synthesized by aldol-like condensations, α-substitution of carbonyl compounds and subsequent elimination, oxidative α,β-dehydrogenation of saturated ketones or aldehydes, and so on) (Wade, 2005, Smith and March, 2001, Nicolaou et al., 2000, Nicolaou et al., 2002, Izawa et al., 2011, Diao and Stahl, 2011, Bigi and White, 2013, Huang and Dong, 2013, Deng et al., 2014, Huang et al., 2015, Jie et al., 2016, Yoshii et al., 2016, Chen et al., 2017) and (2) dienones and dienals bearing substituent groups in various positions could be produced directly. Despite these obvious benefits, to the best our knowledge, the efficient γ,δ-dehydrogenation of enones or enals to produce conjugated dienones or dienals has not been reported so far.

Mechanistically, we conceived that transition metal, especially palladium, could activate the allylic C–H bond to afford a π-allylpalladium intermediate (S1), which could generate a γ-palladation enone or enal (S2) (Patil and Yamamoto, 2006), which then underwent a sequence β-hydride elimination to give conjugated dienyl carbonyl product and PdII-hydride intermediate that underwent reductive elimination and oxidation to complete the catalytic cycle (Scheme 1C). In this protocol, there were two challenges: one is the avoiding the direct oxidation of alkene bond of starting material (e.g., Wacker-type oxidation) and the other is preventing the product from the deeper oxidation (e.g., to generate trienone). To address the challenges, an efficient but mild catalytic oxidative system should be developed.

Results and Discussion

To test this proposal, we chose enone (1aa) as the model substrate to begin our investigation. Initially, various palladium catalysts were examined with DMSO as the solvent and molecular oxygen as the terminal oxidant (Table 1, entries 1–7). Pd(TFA)2, Pd(OAc)2, Pd(PPh3)4, and Pd2(dba)3 reaction systems afforded the desired product 2aa in 38%, 23%, 25%, and 18% yields, respectively, whereas PdCl2 and Pd(PPh3)2Cl2 systems could not react and Pd(OH)2 reaction system only provided trace 2aa. Considering that trifluoroacetic acid (TFA) and Pd(OAc)2 can generate more electropositive [Pd(II)O2CCF3]+ species in situ (Lu et al., 1999, Jia et al., 2000), which is predictably easier to form π-allylpalladium intermediate (Scheme 1C, S1) and γ-palladation enone (Scheme 1C, S2), thereby facilitating the γ,δ-dehydrogenation reaction, 0.2 equiv. of TFA was introduced into Pd(OAc)2-catalyzed reaction system. To our delight, the reaction gave (E,E)-dienone 2aa in 63% yield with complete double bond (E,E)-stereoselectivity (Table 1, entry 8). Then, 0.2 equiv. TFA was added into other palladium-catalyzed reaction systems. Interestingly, the yields of most of the reactions were improved to a certain extent; nevertheless, the result of the combination of Pd(OAc)2 and TFA was still the better (Table 1, entries 9–14). Next, the solvent was screened, and DMSO proved to be the best solvent (Table 1, entries 15–17). After careful investigation of the amount of TFA, 2.0 equiv. TFA provided the highest yield (Table 1, entry 18). Replacing TFA with other acids proved to be either less effective or totally ineffective (Table 1, entry 19). Thus the optimized reaction conditions for the γ,δ-dehydrogenation of 1aa were identified as following: 1aa (0.5 mmol), Pd(OAc)2 (10 mol%), and TFA (2.0 equiv.) under oxygen atmosphere in DMSO at 80°C.

Table 1.

Optimization of the Reaction Conditions

Inline graphic
Entry Pd source TFA (equiv.) Solvent Yielda (%)
1 Pd(TFA)2 – DMSO 38
2 Pd(OAc)2 – DMSO 23
3 Pd(PPh3)4 – DMSO 25
4 Pd2(dba)3 – DMSO 18
5 PdCl2 – DMSO NR
6 Pd(PPh3)2Cl2 – DMSO NR
7 Pd(OH)2 – DMSO Trace
8 Pd(OAc)2 0.2 DMSO 63
9 Pd(TFA)2 0.2 DMSO 51
10 Pd(PPh3)4 0.2 DMSO 48
11 Pd2(dba)3 0.2 DMSO 56
12 PdCl2 0.2 DMSO Trace
13 Pd(PPh3)2Cl2 0.2 DMSO NR
14 Pd(OH)2 0.2 DMSO 59
15 Pd(OAc)2 0.2 DMF 25
16 Pd(OAc)2 0.2 CH3CN 50
17 Pd(OAc)2 0.2 THF 20
18b Pd(OAc)2 2.0 DMSO 73
19c Pd(OAc)2 2.0 DMSO <13
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Reaction conditions: Unless otherwise noted, the reaction was carried out with 1aa (0.5 mmol), [Pd] (10 mol %) in solvent (2.5 mL) under O2 (1 atm) atmosphere at 80°C for 12 h.

a

Isolated yield.

b

Amount of TFA: 0.1 equiv. (30%), 0.2 equiv. (63%), 0.5 equiv. (66%), 1.0 equiv. (68%), 1.5 equiv. (70%), 3.0 equiv. (68%).

c

Other acid (1.0 mL): for hydrochloric acid and benzoic acid, no product; AcOH and TsOH, trace product; CF3SO3H, 12% yield.

With the optimized reaction conditions in hand, we next surveyed the substrate scope (Scheme 2A). First, the length of carbon chain of enones was increased to check if further oxidation could happen. Delightedly, all of them only provided the desired (E,E)-dienones in 70%–79% yields and no further oxidative product (e.g., trienone) was observed (Scheme 2A, 2aa-2ag). Substitutions at each position (i.e., α-, β-, γ-, or δ-positions or beyond), despite their increasing steric hindrance, were all well-tolerated (2ah-2am). Note that the γ,δ-dehydrogenation could occur not only on aliphatic chain but also on aliphatic cycles (2aj). Interestingly, a steroid compound 1am also successfully underwent the γ,δ-dehydrogenation to give 6-testosterone (2am) in good yield. This case together with 2al showed that the current catalytic reaction conditions preferred γ,δ-dehydrogenation to α,β-dehydrogenation, highlighting the advantage of the process for the synthesis of dienones. δ-Aryl-substituted enones could also be γ,δ-dehydrogenated in excellent yields (2an-2ap). It is noteworthy that, in all cases, only E,E-isomers were obtained, and no Z-isomers can be detected by analyzing the reaction mixtures.

Scheme 2.

Scheme 2

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Substrate Scope of the Palladium-Catalyzed γ,δ-Dehydrogenation of Enones and Enals

(A) Dehydrogenation of aliphatic enones.

(B) Dehydrogenation of aryl enones.

(C) Dehydrogenation of enals.

Next, we investigated another kind of enones, aryl enones (Scheme 2B). 1-Arylhept-2-en-1-ones bearing either electron-donating or electron-withdrawing groups all reacted smoothly to provide the desired dienones in good yields (2ba-2bc). Increasing the length of the alkyl chain (2bd-2bh) or changing the straight chain to branched chain (2bi) or aliphatic cycle (2bj) was permitted. A series of substituted (E)-1,5-diphenylpent-2-en-1-ones (1bk-1bt) were also investigated. The results indicated that both the position (o-, m- or p-) and the electronic properties (electron-donating or electron-withdrawing property) of substitution groups did not affect the dehydrogenation and that they all afforded the corresponding (E,E)-dienones in 73%–81% yields. The other aromatic substrate, naphthyl enone, was also suitable for the reaction to give dienone 2bu in good yields. Again, only E,E-isomers were obtained. The structure of 2bt was confirmed by single-crystal X-ray diffraction (see Supplemental Information).

Then, we focused on the γ,δ-dehydrogenation of enals, which were challenging substrates due to the aldehyde's susceptibility toward oxidation under oxidative conditions (Padala and Jeganmohan, 2012, Liu et al., 2015, Santhoshkumar et al., 2015) and undesired metal insertion into an acyl C−H bond (Bosnich, 1998, Fristrup et al., 2008, Garralda, 2009, Jun et al., 2007, Leung and Krische, 2012, Modak et al., 2012, Murphy and Dong, 2014, Willis, 2010). Pleasingly, all enals worked well as enones to produce the desired (E,E)-dienals in good to excellent yields, and the susceptible aldehyde group remained intact, indicating that the oxidative dehydrogenation conditions were very mild (Scheme 2C). The reaction also only provided E,E-isomers, and no Z-isomers could be detected.

To test the practicality of the method, a large-scale experiment has been carried out. With the above-mentioned standard reaction conditions, 1bu (747 mg, 2.6 mmol) was converted into the desired dienone 2bu (556 mg) in 75% yield (Scheme 3A). Notably, when the catalyst loading was reduced to 6 mol %, the yield was not decreased, although more reaction time was required.

Scheme 3.

Scheme 3

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The Practicality of the Palladium-Catalyzed γ,δ-Dehydrogenation of Enones and Enals

(A) Large-scale experiment.

(B) Synthesis of piperine.

To highlight the synthetic utility of this methodology, we employed it as a key step to rapidly synthesize a natural product, piperine, an alkaloid responsible for the pungency of black pepper and long pepper. Recent investigations have shown that piperine has diverse bioactivities including chemopreventive, antioxidant, immunomodulatory, anticarcinogenic, stimulatory, hepatoprotective, anti-inflammatory, antimicrobial, and antiulcer activities (Doucette et al., 2013, Gorgani et al., 2017). Enal 3ad was converted into (E,E)-dienal 4ad under standard conditions, followed by oxidation with Jones reagent to acid and the condensation with piperidine to give piperine in three steps in 54% overall yield (Scheme 3B).

To gain insight into the reaction mechanism, we carried out a series of kinetic isotope effect (KIE) experiments (Scheme 4). The KIE value of two parallel competition reactions of 1an and γ-deuterated [D2]-1an was found to be 6.0 (Scheme 4A), and the intramolecular KIE value for the reaction of δ-deuterated [D]-1an was 1.2 (Scheme 4B). These results showed that the cleavage of the γ-C−H bond should be involved in the rate-determining step, whereas the elimination of δ-C−H bond was fast and not rate limiting. The complete E,E-stereoselectivity of dienones and dienals might be attributed to the formation of the thermodynamically more stable E-product at β-hydride elimination step in the current heating reaction conditions (80°C) and also to the probable presence of Pd-mediated isomerization of olefins under the current Pd-catalyzed reaction system (Bond and Hellier, 1965, Stang and White, 2011). In the reaction system, there were the nucleophilic TFA and H2O, which could react with π-allylpalladium intermediate (Chen and White, 2004, Chen et al., 2005), but we could not detect any corresponding product, which probably could be ascribed to the fast β-hydride elimination of γ-palladation S2, or the fast elimination of TFA or H2O of the corresponding –O2CCF3- or –OH-substituted products under the current acidic reaction conditions. In-depth studies are currently underway to fully elucidate the mechanistic details.

Scheme 4.

Scheme 4

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Kinetic Isotope Effect

(A) The KIE value of two parallel competition reactions of 1an and γ-deuterated [D2]-1an.

(B) The intramolecular KIE value for the reaction of δ-deuterated [D]-1an.

Conclusion

In summary, we have developed a new strategy for the synthesis of conjugated (E,E)-dienones and (E,E)-dienals via a palladium-catalyzed aerobic γ,δ-dehydrogenation of enones and enals. Compared with the previous methods, the biggest advantage of the method is the generality. The method can be employed in the direct and efficient synthesis of various (E,E)-dienones and (E,E)-dienals, including non-substituted and α-, β-, γ-, and/or δ-substituted (E,E)-dienones and (E,E)-dienals. Another advantage of the method is the ready accessibility and elaboration of the starting materials, enones and enals, some of which are commercially available, and they also can be easily obtained by conventional approaches. Furthermore, the reaction is of complete E,E-stereoselectivity and uses molecular oxygen as the sole clean oxidant. Owing to mild reaction conditions and good functional group compatibility, the approach should have broad applications in organic synthesis, medical, and material chemistry.

Limitations of the Study

α,β-Unsaturated amides, acids, and ester provided the γ,δ-dehydrogenated products in low yields under the current reaction conditions.

Methods

All methods can be found in the accompanying Transparent Methods supplemental file.

Acknowledgments

We are grateful for financial support from National Natural Science Foundation of China (NSFC-21572178 and NSFC-21702162), Natural Science Basic Research Plan in Shaanxi Province of China (Program No. 2017JM2006), and the Key Science and Technology Innovation Team of Shaanxi Province of China (2017KCT-37).

Author Contributions

G.-F. P. and X.-L. Z. contributed equally to this work. G.-F. P. and Y.-Q. W. conceived the project and designed the experiments. G.-F. P., X.-L. Z., X.-Q. Z., and R.-L. G., performed and analyzed the experiments. G.-F. P. and Y.-Q. W. wrote the manuscript. All the authors discussed the results and commented on the manuscript.

Declaration of Interests

The authors declare no competing interests.

Published: October 25, 2019

Footnotes

Supplemental Information can be found online at https://doi.org/10.1016/j.isci.2019.09.027.

Data and Code Availability

The structures of 2bt reported in this article have been deposited in the Cambridge Crystallographic Data Center under accession numbers CCDC: 1892057.

Supplemental Information

Document S1. Transparent Methods and Figures S1–S110
mmc1.pdf (4.3MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Document S1. Transparent Methods and Figures S1–S110
mmc1.pdf (4.3MB, pdf)

Data Availability Statement

The structures of 2bt reported in this article have been deposited in the Cambridge Crystallographic Data Center under accession numbers CCDC: 1892057.

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