Access to Densely Functionalized Chalcone Derivatives with a 2

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Access to Densely Functionalized Chalcone Derivatives with a 2‑Pyridone Subunit via Pd/Cu-Catalyzed Oxidative Furan−Yne Cyclization of N‑(2-Furanylmethyl) Alkynamides under Air Yongjie Yang,† ChengCheng Fei,‡ Kai Wang,§ Bo Liu,§ Dingxin Jiang,*,‡ and Biaolin Yin*,† †

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 ‡ Key Laboratory of Natural Pesticide and Chemical Biology, Ministry of Education, Laboratory of Insect Toxicology, South China Agricultural University, Guangzhou 510642, P. R. China § Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510006, P. R. China S Supporting Information *

ABSTRACT: A protocol for synthesis of chalcone derivatives with a 2pyridone subunit from N-(2-furanylmethyl) alkynamides is reported. This synthesis involves Pd/Cu-catalyzed oxidative furan−yne cyclization at room temperature in air and may proceed via nucleopalladation of the alkyne to form a vinylpalladium intermediate, with a furan ring acting as the nucleophile.

T

furans with terminal alkynes to furnish phenols through a cyclopropyl metal-carbene intermediate formed by exocyclization of the alkyne with the C2−C3 double bond of the furan ring (Scheme 1, eq 3).4 Finally, gold-catalyzed furan−yne endo-cyclization accompanied by furan ring opening has been shown to give enal or enones (Scheme 1, eq 4).5 Owing to the varied and useful chemistry of furans6 and alkynes, particularly chemistry mediated by transition-metal catalysts and/or Lewis acids, the development of novel furan−yne cyclization methods continues to be an active area of research. Pd-catalyzed transformation of functionalized alkynes7 is a powerful method for the efficient formation of carbon−carbon and carbon−heteroatom bonds. Various nucleophiles, including acetic acid, amides and amines, halides and pseudohalides, and boronic acids, have been used for nucleopalladation of alkynes to generate the corresponding vinylpalladium species, which can then react with carbon monoxide,8 boronates,9 halides and pseudohalides,10 unactivated olefins,11 allylic alcohols,12 acrylic aldehydes,13 allyl acid,14 allyl esters, 15 cyanides,16 and isocyanides17 to afford difunctionalized alkynes.18 The development of new coupling partners for difunctionalization of alkynes can be expected to expand the synthetic applications of this method. Given that the aromatic furan ring is electron-rich and often acts as a nucleophile, we hypothesized that nucleopalladation of alkynes 1 bearing a pendant furan ring would generate vinylpalladium intermediate A, which could then couple with various partners to provide access to chalcone derivatives 2, some of which show bioactivities19 and interesting photoelectronic properties20 (Scheme 1, eq 5). Chalcones are

he development of efficient methods for carbo- and heterocycle synthesis is an important area of research in organic chemistry.1 One method that has proven to be versatile for this purpose is the intramolecular cyclization of furan−ynes. Four main strategies for furan−yne cyclization have been reported. One strategy is Friedel−Crafts-type reaction of 4-, 5-, and 6-aryl-1-ynes with catalysis by electrophilic metal halides to afford furan-fused bicyclic compounds (Scheme 1, eq 1).2 A second strategy is the intramolecular [4 + 2] cycloaddition of furans with alkynes to afford oxabicyclic compounds, which can be cleaved to form phenols. In such reactions, the alkyne that acts as a dienophile is usually activated by η2-coordination to a metal halide or by the influence of an electron-withdrawing substituent (Scheme 1, eq 2).3 A third strategy is the reaction of Scheme 1. Intramolecular Cyclizations of Furan−Ynes

Received: February 21, 2018

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.8b00618 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

revealed that CuBr2 was optimal (Table 1, entries 11−15). Replacing DCE with DCM, THF, MeCN, toluene, acetone, MeOH, or DMF did not improve the yield (Table 1, entries 16−22). Both PdBr2 and CuBr2 were essential: in the absence of either catalyst, no 2a was detected (Table 1, entries 23 and 24). Thus, we concluded that the optimal conditions involved the use of PdBr2 (10 mol %) and CuBr2 (20 mol %) as the catalysts, LiBr (2 equiv) as the bromide source, and DCE as the solvent at room temperature under an air atmosphere (Table 1, entry 2). With the optimized conditions in hand, we explored the substrate scope with respect to the R1 substituent on the furan ring (Table 2). For this purpose, we used substrates 1 with a

generally synthesized via aldol reactions between aldehyde and ketone substrates, but the preparation of the substrates tends to be difficult, requiring multiple steps if they are structurally complex and/or densely functionalized. As part of our ongoing work on the synthetic applications of furans,21 we herein report a protocol for the synthesis of densely functionalized chalcone derivatives 2 with a 2-pyridone subunit22 via a Pd/Cu-catalyzed furan−yne oxidative cyclization reaction of N-(2-furanylmethyl) alkynamides, in which both the furan ring and an external halide act as nucleophiles and air serves as the terminal oxidant at room temperature. The success of the protocol relied on the development of reaction conditions to suppress side reactions such as [4 + 2] cycloaddition to form a fused phenol and Friedel−Crafts-type reactions to form a fused furan. To optimize the reaction conditions, we used alkynamides 1a as the substrate (Table 1).

Table 2. Substrate Scope with Respect to R1a

Table 1. Optimization of Reaction Conditionsa

entry

[Pd]

[Cu]

solvent

yield (%)b

1 2 3 4 5 6 7 8 9c 10d 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Pd(OAc)2 PdBr2 Pd(TFA)2 PdCl2 Pd(PPh3)2Cl2 Pd(CH3CN)2Cl2 Pd(PPh3)4 Pd2(dba)3 PdBr2 PdBr2 PdBr2 PdBr2 PdBr2 PdBr2 PdBr2 PdBr2 PdBr2 PdBr2 PdBr2 PdBr2 PdBr2 PdBr2 PdBr2 −

CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuSO4 Cu(OAc)2 Cu(OTf)2 Cu(TFA)2 CuCl2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 − CuBr2

DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCM THF MeCN toluene acetone CH3OH DMF DCE DCE

76 80 70 76 ND 41 ND 29 10 37 41 70 63 trace 63 51 ND ND trace ND trace ND ND ND

entry

R1

2 (yield %)b

1 2 3 4 5 6 7 8c 9c 10c 11c 12c 13 14

Ph 4-Me-C6H4 4-MeO-C6H4 3-Me-C6H4 2-Me-C6H4 3,5-di-Me-C6H3 3-F-C6H4 4-F-C6H4 4-Cl-C6H4 4-Br-C6H4 4-CF3-C6H4 3-Me-4-F-C6H4 Me H

2a (76) 2b (79) 2c (79) 2d (76) 2e (72) 2f (77) 2g (71) 2h (55) 2i (48) 2j (57) 2k (50) 2l (60) 2m (60) 2n (68)

a

All the reactions were carried out on 0.4 mmol scale. bIsolated yields are reported. cThis reaction was carried out for 12 h under otherwise standard conditions.

phenyl substituent on the alkyne and an n-Pr group on the amide nitrogen. The reaction was sensitive to the electron density of the furan ring. When R1 was a phenyl group with an electron-donating substituent group (Me or OMe), the corresponding products were obtained in good yields (72− 79%, Table 2, entries 2−6). However, when the R1 phenyl group bore a 4-F, 4-Cl, 4-Br, or 4-CF3 substituent, the yields were relatively low (48−60%, Table 2, entries 7−12). Notably, even when R1 was H or Me, the reaction smoothly gave 2a in 60% and 69% yields, respectively (Table 2, entries 13 and 14). To explore the scope of the protocol with respect to the R2 substituent on the alkyne, we used a series of substrates with a phenyl group on the furan ring and an n-Pr group on the nitrogen (Table 3). From substrates with a phenyl group bearing one or more electron-donating substituents (Me, OMe, or t-Bu), the corresponding products were obtained in moderate to good yields (Table 3, entries 1−6). When R2 was a phenyl group with a halogen atom (F or Cl), the reaction also proceeded smoothly in good yields (Table 3, entries 7−9). However, when R2 was 4-CN-C6H4, no reaction took place (Table 3, entry 10). The exact reason for this failure is not clear at present. When R2 was 4-CF3-C6H4 or Me, complicated product mixtures were obtained, and the yields of 2y and 2z were low (Table 3, entries 11 and 12).

a

All the reactions were carried out on a 0.2 mmol scale. bDetermined by 1H NMR (internal standard: 1,3,5-trimethylbenzene). cN2 was used instead of air. dO2 was used instead of air.

At room temperature in the presence of Pd(OAc)2 (0.1 equiv) and CuBr2 (0.2 equiv) as the catalysts, LiBr (2 equiv) as the added nucleophile, and air as the oxidant, 1a could be transformed into brominated chalcone 2a in 76% yield (Table 1, entry 1). The structure of 2a was assigned on the basis of single-crystal X-ray data obtained for 2ak (see the Supporting Information (SI)). Screening of various other Pd catalysts (Table 1, entries 2−8) indicated that PdBr2 was optimal (Table 1, entry 2). Notably, the yields were lower when the reaction was carried out under nitrogen or oxygen (Table 1, entries 9 and 10). Evaluation of various other Cu catalysts B

DOI: 10.1021/acs.orglett.8b00618 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 3. Substrate Scope with Respect to R2a

Table 5. Synthesis of Chlorinated Chalcone Derivativesa

entry

R2

2 (yield %)b

entry

R1

R2

2 (yield %)b

1 2 3 4 5 6 7 8 9 10 11 12

4-Me-C6H4 4-MeO-C6H4 4-t-Bu-C6H4 3-Me-C6H4 2-Me-C6H4 3,4-di-Me-C6H3 4-F-C6H4 4-Cl-C6H4 3-F-C6H4 4-CN-C6H4 4-CF3-C6H4 Me

2o (70) 2p (66) 2q (75) 2r (63) 2s (63) 2t (70) 2u (76) 2v (75) 2w (75) 2x (ND) 2y (44) 2z (46)

1 2 3 4 5 6

Ph 4-MeO-C6H4 4-F-C6H4 3-Me-4-F-C6H4 Ph Ph

Ph Ph Ph Ph 4-t-Bu-C6H4 4-F-C6H4

2ae (70) 2af (77) 2ag (69) 2ah (74) 2ai (82) 2aj (79)

a

All the reactions were carried out on a 0.4 mmol scale. bIsolated yields are reported.

Scheme 2. Control Experiments

a

All the reactions were carried out on a 0.4 mmol scale. ND = not detected. bIsolated yields are reported.

Finally, substrates with various R3 groups on the amide nitrogen were screened (R1 = R2 = Ph, Table 4). When R3 was Table 4. Substrate Scope with Respect to R3a

entry

R3

2 (yield %)b

1 2 3 4

iPr t-Bu Bn H

2aa (51) 2ab (trace) 2ac (74) 2ad (ND)

Scheme 3. Proposed Reaction Mechanism

a

All the reactions were carried out on a 0.4 mmol scale. ND = not detected. bIsolated yields are reported.

a sterically bulky iPr group, the yield dropped dramatically (to 51%), and when R3 was t-Bu, only a trace of 2ab was detected. However, a substrate with a removable Bn group afforded corresponding product 2ac in 74% yield. When R3 was H, no 2ad was detected. To our delight, a range of chlorinated chalcone derivatives could also be synthesized in good yields from 1 with PdCl2 and CuCl2 as catalysts and LiCl as the chloride source (Table 5). Notably, however, a longer reaction time (24 h) was required, possibly because Cl is a weaker nucleophile than Br. To gain insight into the mechanism of this oxidative coupling reaction, we conducted two control experiments (Scheme 2). First, treatment of 1a with AlCl3 (1 equiv) and NBS (1 equiv) in DCE did not give 2a indicating that the transition-metal catalysts of palladium and copper were essential to the transformation. Second, compound 3aa, which was detected in the reaction mixture, could not be transformed into 2aa under the standard conditions, suggesting that 2aa did not form via electrophilic bromination of 3aa. On the basis of the above-described results and the results of previous studies of Pd-catalyzed difunctionalization of alkynes,7,19 a plausible mechanism is proposed in Scheme 3. Reaction of 1 with PdX2 provides complex 3, which undergoes nucleopalladation to afford vinylpalladium 4. Subsequent ring

opening gives intermediate 5, which undergoes deprotonation and reductive elimination to furnish 2 and generate Pd(0).23 In the presence of Cu(II) and air, oxidation of Pd(0) to PdX2 completes the catalytic cycle. In summary, we have developed a simple, practical protocol for access to densely functionalized chalcone derivatives with a 2-pyridone subunit from N-(2-furanylmethyl) alkynamides. This protocol, which proceeds at room temperature, involves a novel Pd-catalyzed oxidative difunctionalization reaction of alkynes using furan rings as a nucleophile and air as the terminal oxidant. The protocol opens a new route to vinylpalladium compounds and a new method for transformation of furans into other useful compounds. Further exploration of this reactionincluding variation of the aryl rings of the substrate, trapping of the vinylpalladium with carbon nucleophiles, and evaluation of the bioactivities of the productsis underway in our laboratory. C

DOI: 10.1021/acs.orglett.8b00618 Org. Lett. XXXX, XXX, XXX−XXX

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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.8b00618. Details about experimental conditions, characterization data, copies of 1H and 13C NMR spectra of all new compounds (PDF) Accession Codes

CCDC 1822466 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

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

Biaolin Yin: 0000-0002-2547-0231 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by grants from the National Program on Key Research Project (No. 2016YFA0602900), the National Natural Science Foundation of China (No. 21572068), the Science and Technology Program of Guangzhou, China (No. 201707010057), Guangdong Natural Science Foundation (No. 2017A030312005), and the Science and Technology Planning Project of Guangdong Province, China (Nos. 2017A020216021 and 2014A020221035).

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REFERENCES

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DOI: 10.1021/acs.orglett.8b00618 Org. Lett. XXXX, XXX, XXX−XXX