Nucleo-Palladation-Triggering Alkene Functionalization: A Route to γ

Letter Cite This: Org. Lett. 2017, 19, 5756-5759

pubs.acs.org/OrgLett

Nucleo-Palladation-Triggering Alkene Functionalization: A Route to γ‑Lactones Meifang Zheng, Pengquan Chen, Liangbin Huang, Wanqing Wu,* and Huanfeng Jiang* Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China S Supporting Information *

ABSTRACT: An unprecedented strategy for the highly effective synthesis of γ-lactones from homoallylic alcohols was achieved by palladium catalysis in one step. The protocol affords aryl, alkyl, and spiro γ-lactones directly from readily available homoallylic alcohols in good yields with excellent functional group tolerance and high chemoselectivity under mild conditions.

P

ygenase oxidation of cyclic ketones.6 However, the substrate scope accessed by this strategy tends to be limited due to the use of a strong acid. Besides, ring-closure techniques starting from the hydroxy ester precursors 7 and the alcohol dehydrogenase oxidation of diols8 have been reported. However, they required the preparation of diols or acidic derivatives. Additionally, the chemical synthesis of lactones from the cyclization of Ω-hydroxycarboxylic acids, esters, or their activated derivatives play a dominant role.9 The insertion of CO to allylic alcohols also provides a new avenue for lactone synthesis.10 Yang’s group reported a gold-catalyzed method from alkynyl acid.11 Moreover, we have previously developed a Cu-catalyzed [3 + 2] cycloaddition of styrene for the construction of γ-lactone skeletons.12 Although several synthetic methods for γ-butyrolactones have been reported, in view of the significance of the lactone derivatives, the development of more direct, simple, and efficient routes to access γ-butyrolactones is always in high demand. Therefore, we envisioned that a direct route would be possible from βhydroxyalkenes via a novel Pd-catalyzed oxidative cyclization to lactones. As a start, we selected 1-phenylbut-3-en-1-ol (1a) as the model substrate, which was easily prepared from benzaldehyde and allylmagnesium bromide (Table 1). As expected, when TBHP (tert-Butyl hydroperoxide) was used as an oxidant, an 11% yield of the expected product 2a was obtained (Table 1, entry 1). To our delight, altering the solvent from CH3CN to CH3NO2 led to the corresponding product 2a in 74% yield (Table 1, entry 3). Screening of the solvents showed the efficiency of CH3NO2 was higher than other solvents (see the Supporting Information, Table S1). Further investigation indicated that the addition of TBHP as the oxidant led to a higher yield of 2a than other oxidants (Table 1, entries 4−9). Other additives, such as CuCl, In(OTf)3, and FeCl3, gave an inferior yield compared with that of CuCl2 (Table 1, entries

alladium-catalyzed reactions have a profound impact in organic synthesis, due to their ability to form C−C, C−N, and C−O bonds with high efficiency in a highly designated fashion. Well-known Pd-catalyzed reactions, such as Suzuki coupling, Wacker oxidation, and Hartwig−Buchwald reaction, have extensive applications in industry productions.1 For example, palladium catalysis has been applied to intermolecular C−O bond formation with γ-hydroxyalkenes as a substrate by Wolfe’s group.2 For a long time, our group has been dedicated to constructing various C−C, C−N, and C−O bonds via nucleopalladation processes. Halopalladation, aminopalladation, and oxypalladation designed with high efficiency and easy operation have been reported.3 The γ-lactone core and its derivatives exist in more than 15 000 natural products, including antibiotic and antitumor reagents.4 Stemming from the medicinal importance of molecules such as those described above, there has been a longstanding interest in the synthesis of this moiety for organic chemists.5 At present, many elegant strategies have been designed to prepare γ-lactones (Scheme 1). One general method for these substructures is Baeyer−Villiger monooxScheme 1. Previous Synthetic Methods for Lactones

Received: August 28, 2017 Published: October 26, 2017 © 2017 American Chemical Society

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DOI: 10.1021/acs.orglett.7b02688 Org. Lett. 2017, 19, 5756−5759

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

entrya

catalyst

additive

oxidant

solvent

yield (%)b

1 2 3 4 5 6 7 8 9 10c 11 12 13 14 15 16d 17 18e 19 20f

PdCl2 PdCl2 PdCl2 PdCl2 PdCl2 PdCl2 PdCl2 PdCl2 PdCl2 PdCl2 PdCl2 PdCl2 PdCl2 Pd(OAc)2 Pd(CH3CN)2Cl2 PdCl2 − PdCl2 PdCl2 PdCl2

CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 CuCl In(OTf)3 FeCl3 CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 − CuCl2

TBHP DTBP TBHP DTBP PhI(OAc)2 DDQ H2O2 O2 BQ TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP

CH3CN CH3CN CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2 CH3NO2

11 50 74 60 21 7 15 13 12 57 34 10 17 14 46 57 n.d. 68 10 25

Reaction conditions: unless otherwise noted, the reaction was carried out with 0.5 mmol of 1a and in solvent (1 mL) at 80 °C for 24 h. bYield determined by GC-MS with dodecane as internal standard. n.d. = not detected. c2 equiv of NaHCO3 were added. dThe reaction was carried out with 5 mol % of PdCl2. eThe reaction was carried out with 10 mol % of CuCl2. fThe reaction was carried out at 50 °C for 24 h. a

11−13). Other palladium loadings, such as Pd(OTf)2 and Pd(CH3CN)2Cl2, showed lower efficiency compared with PdCl2 (Table 1, entries 14−16). No reaction was observed in the absence of a palladium catalyst (Table 1, entry 17), while in the absence of CuCl2, a 10% yield of product 2a was detected (Table 1, entry 19). Also, lower temperature was tested for this reaction in which a 25% yield of the desired lactone 2a was obtained (Table 1, entry 20). Major efforts were then made to further optimize the intramolecular alkene functionalization in order to extend its methodology scope. Several bidentate ligands were examined using homoallylic alcohol 1a as the benchmark testing substrate (Table 2). The screening of the ligands revealed L5 leading to a remarkable yield of 2a up to 86% (85% isolated yield). However, the use of L3 was found to be inactive (Table 2, entry 3), and the use of L2 together with PdCl2 led to a sharp decrease in the yield of 2a to 5% (Table 2, entry 4). Employing L4 in the coupling reaction afforded 2a in 75% yield (Table 2, entry 5). Thus, we choose the conditions in Table 2, entry 5 as the standard conditions. Having established the optimal conditions, we next investigated the substrate scope of the reaction with various homoallylic alcohols (Scheme 2). Alcohols with a 4-Me, 3-Me, or 2-Me substituent offered the corresponding products 2b−2d in 83%, 79%, and 65% yields, respectively. We also examined a tert-butyl substituted substrate, which went through the process smoothly and gave a 45% yield of compound 2f. Halogensubstituted substrates worked well with good group tolerance, producing the desired lactones 2h−2j in the yields of 62%, 87%, and 77%, respectively. The transformation of a naphthyl substituted substrate (1k) could also proceed well under the

Table 2. Screening of Ligands for the Optimal Reaction Conditionsa

entrya

ligand

yield (%)b

1 2 3 4 5 6 7c

L1 L2 L3 L4 L5 L6 L5

10 5 n.d. 75 86 (85) 66 77

a

Reaction conditions: unless otherwise noted, the reaction was carried out with 1a (0.5 mmol), PdCl2 (10 mol %), L (12 mol %), CuCl2 (20 mol %), TBHP (1 mmol), and H2O (1 mmol) in CH3NO2 (1 mL) at 80 °C for 24 h. bYield determined by GC with dodecane as internal standard, and isolated yield is in the parentheses. n.d. = not detected. c 25 mol % L5 was added.

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DOI: 10.1021/acs.orglett.7b02688 Org. Lett. 2017, 19, 5756−5759

Letter

Organic Letters Scheme 2. Synthesis of Lactonesa

Scheme 3. 18O-Labeling Experiment

a novel Pd(II)-catalyzed tandem process is proposed (Scheme 4). Initial coordination of the internal alkene to Pd(II) affords Scheme 4. Possible Catalytic Cycle

intermidiate A.2a Subsequently, the π system of CC bond inserts into the [Pd]−O bond to form palladacycle B, followed by β-H elimination to give intermediate C. Then, the nucleophilic addition of water to C generates the intermediate D.15 Subsequent β-H elimination produces enol E. Consequently, the keto−enol tautomerism of intermediate E produces the target product 2a. And the Pd(II) species is regenerated by [Cu]/TBHP to complete the catalytic cycle.17 The alternative mechanism is via the Wacker process, as shown in Cycle B. The anti-Markovnikov selectivity of the Wacker process of intermediate A affords intermediate F. Subsequent keto−enol tautomerism of intermediate G produces the aldehyde H. Then, the cyclization of intermediate H affords the final product 2a.18 However, the mechanism is still unresolved.19 In conclusion, a novel and useful method has been developed to construct lactones via a Pd-catalyzed intermolecular cyclization reaction of homoallylic alcohols. This protocol provides an efficient route to functionalized lactones with easily accessible substrates and mild conditions with good to excellent yields. Ongoing research involves further investigations of the synthetic application, and detailed mechanistic studies are underway in our laboratory.

a

Reaction conditions: unless otherwise noted, the reaction was carried out with 1 (0.5 mmol), PdCl2 (10 mol %), L5 (12 mol %), CuCl2 (20 mol %), TBHP (1 mmol), and H2O (1 mmol) in CH3NO2 (1 mL) at 80 °C for 24 h. Yields refer to the isolated yields. b1 mmol of 1a was tested under the standard conditions. cThe reaction was carried out with solvent CH3CN.

optimized reaction conditions to afford product 2k. Gratifyingly, substrates containing an α-methyl or a β-methyl substituent were found to be a suitable substrate with high selectivity, giving the corresponding products 2m−2p in good yields. Aliphatic alcohols also worked well and converted to the desired lactones 2q and 2r efficiently. Particularly, spiro product 2q was obtained in 68% yield. Moreover, a 31% yield of 5-styryldihydrofuran-2(3H)-one (2s) was afforded with using 1-phenylhexa-1,5-dien-3-ol (1s) as the substrate. However, alkynyl substituted homoallylic alcohol could not transfer to the corresponding product 2t. Besides, when 2vinylphenol was subjected to the system instead of γhydroxyalkenes under the standard conditions, the desired benzofuran-2(3H)-one (2u) was obtained in 35% yield, in which the core is shared by several biologically relevant molecules.13 Critical evidence was obtained in the isotope labeling experiments by using TBHP in a H2O18 solution (Scheme 3).16 The reaction in CH3NO2 led to the formation of [18O]-2a and 2a with a ratio of 1:1, and this result was confirmed by high resolution mass spectrometry (see the Supporting Information for details). Based on the experimental results and previous reports,2,14−16 a tentative mechanism for γ-lactone synthesis via

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02688. Typical experimental procedure and characterization for all products (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. 5758

DOI: 10.1021/acs.orglett.7b02688 Org. Lett. 2017, 19, 5756−5759

Letter

Organic Letters ORCID

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Liangbin Huang: 0000-0001-9450-9454 Huanfeng Jiang: 0000-0002-4355-0294 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the National Key Research and Development Program of China (2016YFA0602900), the National Natural Science Foundation of China (21672072 and 21420102003), and the Fundamental Research Funds for the Central Universities (2015ZY001 and 2017ZD062) for financial support.

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DOI: 10.1021/acs.orglett.7b02688 Org. Lett. 2017, 19, 5756−5759