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Brief Report

Preparation of Dibenzofurotropones via Pd-Catalyzed Cyclization

by
Yu-Wei Lin
and
Shiuh-Tzung Liu
*
Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan
*
Author to whom correspondence should be addressed.
Reactions 2024, 5(1), 111-119; https://doi.org/10.3390/reactions5010005
Submission received: 8 December 2023 / Revised: 9 January 2024 / Accepted: 19 January 2024 / Published: 22 January 2024
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Abstract

:
A synthetic approach to dibenzofurotropone derivatives 1 has been developed through the palladium-catalyzed cyclization of (2-bromoaryl)(3-arylfuran-2-yl)methanones 2 via the activation of arylic C–H bonds. Compounds 2 were easily prepared from the palladium-promoted acyl migration and cyclization of (Z)-pent-2-en-4-yn-1-yl acetates 3 in the presence of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), followed by oxidative decarbonylation and oxidation with O2. Ten new tropone compounds are reported and these compounds show absorption in the UV-vis region and emission in the visible region.

1. Introduction

Tropones, a class of non-benzenoid aromatic compounds, have been found in numerous natural products, showing distinct biological activities [1,2,3,4,5]. Aryl-annulated tropone derivatives such as benzotropones [6,7,8,9,10,11,12,13,14,15,16,17] and furotropones [18,19,20,21,22,23] are also attractive molecules because their extended conjugations might exhibit intriguing chemical and photophysical properties (Figure 1A). Considering their application potential, the development of synthesizing tropones annulated with three aromatic rings (Figure 1B) has attracted substantial interest in material chemistry [11,12,13,14,15,16,17].
Various strategies have been developed for the synthesis of tribenzotropone derivatives I involving Diels−Alder reactions of dibenzotropones [15,16,17], Friedel−Crafts reactions of terphenyl carboxylic acids [17], cyclotrimerization of diynes [10], diazotization followed by 1,3-rearrangement of 9-o-aminophenyl-9-fluorenol [11], and Pd-catalyzed decarboxylative cyclization of 2-iodobiphenyls and 2-(2-bromophenyl)-2-oxoacetic acid [15]. Compared to tribenzotropones, methods to access hetero-aryl-annulated benzotropones derivatives are less often reported. For example, compound II was obtained from the Diels–Alder reaction of 1H-1,4-epoxytribenzo[7]annulen-9(4H)-one with 3,6-diphenyl-1,2,4,5-tetrazine followed by the elimination of N2 and retro-Diels–Alder reaction (Scheme 1) [20]. Besides II, other isomeric dibenzofurotropones, such as dibenzo[2,3-b]furotropones, are not known.
The palladium-catalyzed direct C–H arylation of arenes with aryl halides ought to be one of the most powerful tools for C-C bond formation, typically for the construction of a carbocycles [24,25,26,27,28,29]. In this work, we would like to report an approach for the preparation of dibenzo[2,3-b]furotropones 1 via the palladium-catalyzed oxidative addition of C-Br in 2 followed by C-H activation/cyclization leading to the desired tropones 1 (Scheme 2).

2. Materials and Methods

2.1. Materials and Instrumentation

All chemicals were purchased commercially and used without further purification. Flash chromatography was performed using silica gel 230–400 mesh. 1H and 13C NMR spectra were recorded on a 400 MHZ spectrometer in CDCl3 referenced to TMS. Melting points were determined using a Fargo MP-1D instrument. UV-VIS and fluorescence spectra were determined on JASCO V-670 EX and HITACHI F450 spectrophotometers, respectively. Unless otherwise noted, all the reactions were performed under a nitrogen atmosphere without any other precautions. Compounds 2 were prepared according to our reported procedure [30].

2.2. General Procedure for Preparation of 2

A mixture of 3 (2.5 mmol) and Pd(OAc)2 (0.125 mmol) was dissolved in ethyl acetate (10 mL) with stirring. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.6 mL, 12.5 mmol) was then added and the resulting mixture was heated in an oil bath at 65 °C for 1.5 h under a nitrogen atmosphere. After the reaction, ethyl acetate (10 mL) was added to dilute the solution and was washed with brine (10 mL × 2). The organic layer was collected, dried with anhydrous MgSO4 and concentrated. The residue was filtrated through silica gel with an elution of ethyl acetate/hexane to give the desired crude product 4 upon concentration, which was subjected to the next step without further purification. A mixture of 4 and DBU (5 eq.) in acetonitrile (2 mL) was heated in an oil bath at 65 °C under an oxygen atmospheric environment for overnight. Ethyl acetate (15 mL) was added and washed with brine (10 mL × 2). The organic extract was dried with anhydrous MgSO4 and concentrated. The residue was chromatographed on silica gel with an elution of ethyl acetate/hexane to yield the desired product 2 upon concentration.

2.3. General Procedure for Preparation of Tropones 1

A mixture of 2 (0.2 mmol), Pd(OAc)2 (0.02 mmol, 10 mol%), PCy3·HBF4 (0.04 mmol) and Cs2CO3 (0.24 mmol) was placed in a 10 mL reaction tube. The reaction tube was evacuated and flashed with N2. DMSO (2 mL) was added and the tube was immersed to a pre-heated oil bath at 140 °C. After stirring for 20 h, the reaction mixture was cooled to room temperature and brine (20 mL) was added. This mixture was extracted with ether (30 mL × 3). The extracts were dried and concentrated, and the residue was chromatographed on silica gel with an elution of ethyl acetate/hexane (5/95) giving a colored band, which was collected and concentrated to give the desired product 1.

2.4. Spectroscopic Characterization

(2-Bromophenyl)(3-(4-chlorophenyl)-5-(p-tolyl)furan-2-yl)methanone (2aa). Pale yellow solid (383 mg, 38%); m.p.: 92–93 °C; Eluent: ethyl acetate:hexane = 3:97; 1H NMR (400 Mz, CDCl3) δ 7.62 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.4 Hz, 3H), 7.48 (dd, J = 7.9, 1.1 Hz 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.33–7.28 (m, 4H), 7.24 (d, J = 8.0Hz, 2H), 6.90 (s, 1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 183.2, 157.6, 145.1, 140.6, 140.0, 137.8, 134.5, 132.9, 131.2, 130.4, 130.1, 129.6, 129.5, 128.2, 127.0, 126.1, 125.1, 120.2, 109.3, 21.4. IR (KBr) υC=O 1648 cm−1. HRMS (ESI-TOF) m/z [M + H]+ Calcd. for C24H17BrClO2: 451.0095. Found: 451.0090.
2-Chloro-6-(p-tolyl)-8H-dibenzo[3,4:5,6]cyclohepta[1,2-b]furan-8-one (1aa). Pale yellow solid (65.9 mg, 89%); m.p.: 194–195 °C; Eluent: ethyl acetate:hexane = 5:95; 1H NMR (400 MHz, (CDCl3): δ 8.42 (dd, J = 7.7, 1.7 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.81 (t, J = 8.1 Hz, 3H), 7.72 (td, J = 7.3, 1.1 Hz, 1H), 7.66 (t, J = 7.0 Hz, 1H), 7.53 (dd, J = 8.5, 1.8 Hz, 1H), 7.28 (s, 1H), 7.27 (s, 1H), 7.20 (s, 1H), 2.41 (s,3H); 13C NMR (100 MHz, CDCl3) δ 178.6, 158.1, 149.3, 139.9, 138.4, 138.0, 136.1, 133.9, 132.0, 131.8, 131.6, 131.4, 129.6, 129.5, 129.2, 128.8, 128.6, 126.8, 126.1, 125.3, 104.0, 21.4. IR (KBr) υC=O 1628 cm−1. HRMS (ESI-TOF) m/z [M + H]+ Calcd. for C24H16ClO2: 371.0833. Found: 371.0823.
All spectral data of other compounds can be found in the Supplementary Materials.

3. Results and Discussion

3.1. Preparation and Optimization of Reaction Conditions

Bromo-substituted 2-benzoyl-3-arylfuran derivatives 2 were prepared according to our previously reported method (Scheme 3) [30]. The Pd-promoted cyclization of (Z)-pent-2-en-4-yn-1-yl acetates 3 provided 4, which subsequently underwent decarbonylation followed by oxidation in the air to deliver the desired compounds 1. This multi-step reaction could be subsequently manipulated without the isolation of 4. Compounds 2, used for this study, are summarized in Figure 2. Compounds 2ab–2ag are those with the ortho-bromo substituent at the Ar1 ring, whereas 2ba–2ga are those with the ortho-bromo substituent at the Ar2 ring.
To test the possibility of cyclization leading to tropone, 2aa was selected as a model substrate for screening and the results of the search for the optimization conditions are summarized in Table 1. By using a combination of Pd(OAc)2 and PCy3·HBF4 as the catalyst, running the reaction in DMF for 20 h provided the desired product 1aa at 68% (Table 1, entry 1). By changing to using DMSO as the solvent, 1aa was obtained quantitatively, showing that DMSO is the best medium for this coupling (Table 1, entry 2). When using DBU as the base, the reaction did not provide the desired product (Table 1, entry 4). Shortening the reaction period to 10 h, the yield of 1aa dropped down to 58%. Next, we screened various phosphine ligands for further improvements (Table 1, entries 6–9). It appears that the bulky ligands do assist this cyclization. The reaction was inhibited by the presence of oxygen (Table 1, entry 11). The optimal conditions for this reaction are established as running the reaction of 2aa in the presence Pd(OAc)2/PCy3·HBF4 in DMSO (Table 1, entry 2).
The structure of 1aa was determined by spectroscopic methods. The infrared carbonyl stretching wavenumber of 1aa appears at 1628 cm−1, which is red-shifted by ca. 20 cm−1 in comparison to 2aa. This stretching frequency is similar to those of furotropones [10,11,12,13,14,15,16,17]. Meanwhile, the 13C NMR shift of carbonyl function in 1aa emerges at 178.6 ppm, which resembles those of tropones. HRMS-ESI shows m/z at 371.0823, which is consistent with [M + H]+, implying the formation of a seven-member ring by the elimination of HBr in this reaction.

3.2. Reaction Scope

With the optimized reaction conditions in hand, a series of substrates with bromide modified on the Ar1 ring 2aa–2ag were investigated. As shown in Scheme 4, 2aa–2ad, with various substituted groups at the para position in the Ar2 ring, could provide the corresponding products 1aa–1ad in excellent isolated yields (83–89% yield). We noticed that 2ae underwent the cyclization smoothly to 1ae, giving a 73% yield, showing that the thiophenyl ring is able to proceed with such a reaction via Pd-catalyzed C-H activation. As expected, compound 2af, a reactant with a thiophenyl substituent at C(5) of the furan ring, gave the desired product 1af at a high yield. It is worth mentioning that compound 2ag, with the para bromo substituent in the Ar2 ring, provided 1ad at 7% and a mixture of unidentified products under the optimized reaction conditions. Apparently, de-bromination took place to yield 1ad, but the oxidative addition of C-Br bonds in the Ar2 ring also caused complications in the reaction.
This palladium-catalyzed arylation leading to the tropone ring is also be applied to those with the ortho bromo-substituent in the Ar2 ring (2ba–2ga). Similar to the transformation of 2ad into 1ad, the cyclization of 2ba gave the same product 1ad at a 95% yield [Equation (1)]. However, substrate 2ca, which has o-bromo groups in both the Ar1 and Ar2 rings, did render the expected product 1ad, showing the poor efficiency of the coupling of di-bromide moieties. Other substituents in both the Ar1 and Ar3 ring are also applicable for this cyclization, leading to the corresponding tropones (Scheme 5) and illustrating a possible introduction of various substituents in this methodology.
A possible mechanistic pathway leading the tropone ring is shown in Scheme 6 [24,25,26,27,28,29]. Initially, the oxidative addition of C-Br bond toward the metal center (Scheme 6, step i) gives intermediate I-1, which then undergoes the dissociation of bromide from the metal center to yield I-2 or I-3 (Scheme 6, step ii or iii). The arylic C-H bond is activated by the palladium center to render intermediate I-4 (Scheme 6, step iv). Reductive elimination takes place from the metal center to produce the tropone and regenerates the palladium catalyst, completing the catalytic cycle.

3.3. Photo-Physical Property of Tropones 1

The absorption and emission spectra of the newly prepared dibenzo[3,4:5,6]cyclohepta[1,2-b]furan-8-ones were examined. The spectroscopic data of all the compounds in ethanol (10 μM) are summarized in Table 2. All the compounds have an absorption maximum around 360 nm, giving these compounds a light yellow color. This series of compounds also give emissions in the range of 425~486 nm, showing a slightly substituent effect on the photo-physical property.
Furthermore, we surveyed the absorption and emission spectra of 1ad under various solvent systems. The absorption maximum of n → π* transition in toluene comes at 355 nm, while, in a polar solvent of ethanol, absorption is displayed at 362 nm, suggesting a bathochromic shift of about 7 nm. In addition, the fluorescence emission spectra of 1ad were recorded in different solvents and the results showed that fluorescence emission is also solvent-dependent (Table 3). It appeared that there was a maximum Stokes shift of 86 nm in the ethanol solution. These observations are quite similar to those of furo[2,3-d]tropones, as reported by Ramasastry’s group [19].

4. Conclusions

In summary, we have developed a procedure for the preparation of a series of substituted dibenzo[3,4:5,6]cyclohepta[1,2-b]furan-8-ones via the palladium-catalyzed cyclization of (2-bromoaryl)(3-arylfuran-2-yl)methanones through the activation of arylic C–H bonds. In particular, compound 1ae is the first molecule with three different aromatic rings annulated with tropone (benzothiophenfurotropone). These newly prepared tropones show absorptions around 360 nm and emissions around 440~486 nm. Detailed photophysical studies of the applications of these compounds are currently under investigation.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/reactions5010005/s1, Table S1 Physical and spectral data of 2aa–2ga; Table S2 Physical and spectral data of 1aa–1ga; Figure S11H NMR spectrum of compound 2aa; Figure S2 1H NMR spectrum of compound 2ab; Figure S3 1H NMR spectrum of compound 2ac; Figure S4 1H NMR spectrum of compound 2ad; Figure S5 1H NMR spectrum of compound 2ae; Figure S6 1H NMR spectrum of compound 2af; Figure S7 1H NMR spectrum of compound 2ag; Figure S8 1H NMR spectrum of compound 2ba; Figure S9 1H NMR spectrum of compound 2ca; Figure S10 1H NMR spectrum of compound 2da; Figure S11 1H NMR spectrum of compound 2ea; Figure S12 1H NMR spectrum of compound 2fa; Figure S13 1H NMR spectrum of compound 2ga; Figure S14 1H NMR spectrum of compound 1aa; Figure S15 1H NMR spectrum of compound 1ab; Figure S16 1H NMR spectrum of compound 1ac; Figure S17 1H NMR spectrum of compound 1ad; Figure S18 1H NMR spectrum of compound 1ae; Figure S19 1H NMR spectrum of compound 1af; Figure S20 1H NMR spectrum of compound 1da; Figure S21 1H NMR spectrum of compound 1ea; Figure S22 1H NMR spectrum of compound 1fa; Figure S23 1H NMR spectrum of compound 1ga.

Author Contributions

Conceptualization, S.-T.L.; methodology, investigation, and data collection, Y.-W.L.; writing—original draft preparation, S.-T.L.; data checking and editing, Y.-W.L. and S.-T.L.; supervision, S.-T.L. funding acquisition, S.-T.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Science and Technology, Taiwan (MOST111-2113-M-002-007).

Data Availability Statement

The data reported in this article can be obtained from the authors upon reasonable request.

Acknowledgments

We acknowledge the mass spectrometry technical research services of the NTU Consortia of Key Technologies for mass measurement.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Structures of (A) mono-aryl-annulated tropones [6,7,8,9,10,11,12,13,14,15,16,17,21,22,23] and (B) triaryl-annulated tropones.
Figure 1. Structures of (A) mono-aryl-annulated tropones [6,7,8,9,10,11,12,13,14,15,16,17,21,22,23] and (B) triaryl-annulated tropones.
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Scheme 1. Synthesis of furotropone II via Diels–Alder reactions.
Scheme 1. Synthesis of furotropone II via Diels–Alder reactions.
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Scheme 2. Pd-catalyzed cyclization leading to tropones.
Scheme 2. Pd-catalyzed cyclization leading to tropones.
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Scheme 3. Bezyoyl furan derivatives 2 from acetate of enynol.
Scheme 3. Bezyoyl furan derivatives 2 from acetate of enynol.
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Figure 2. Structures of bromo-substituted 2-benzoyl-3-arylfurans studied in this work.
Figure 2. Structures of bromo-substituted 2-benzoyl-3-arylfurans studied in this work.
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Scheme 4. Pd-catalyzed cyclization with bromide at Ar1 ring. Conditions: 2 (0.2 mmol), Pd(OAc)2 (0.02 mmol), PCy3·HBF4 (0.04 mmol), Cs2CO3 (0.24 mmol) in DMSO (2 mL) at 140 °C for 20 h.
Scheme 4. Pd-catalyzed cyclization with bromide at Ar1 ring. Conditions: 2 (0.2 mmol), Pd(OAc)2 (0.02 mmol), PCy3·HBF4 (0.04 mmol), Cs2CO3 (0.24 mmol) in DMSO (2 mL) at 140 °C for 20 h.
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Scheme 5. Product of Pd-catalyzed cyclization with bromide at Ar2 ring.
Scheme 5. Product of Pd-catalyzed cyclization with bromide at Ar2 ring.
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Scheme 6. Possible pathway leading to the formation of the tropone ring.
Scheme 6. Possible pathway leading to the formation of the tropone ring.
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Table 1. Optimization of reaction conditions 1.
Table 1. Optimization of reaction conditions 1.
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EntryComplex/LigandBase (eq.)SolventTemp./TimeYield 2
1Pd(OAc)2/PCy3·HBF4Cs2CO3 (1.2)DMF140 °C/20 h68%
2Pd(OAc)2/PCy3·HBF4Cs2CO3 (1.2)DMSO140 °C/20 h98%
3Pd(OAc)2/PCy3·HBF4Cs2CO3 (3)DMF140 °C/20 h95%
4Pd(OAc)2/PCy3·HBF4DBU (1.2)DMSO140 °C/20 h-
5Pd(OAc)2/PCy3·HBF4Cs2CO3 (1.2)DMSO140 °C/10 h58%
6Pd(OAc)2/PPh3Cs2CO3 (1.2)DMSO140 °C/20 h42%
7Pd(OAc)2/P(o-tol)3Cs2CO3 (1.2)DMSO140 °C/20 h21%
8Pd(OAc)2/PCy3Cs2CO3 (1.2)DMSO140 °C/20 h78%
9Pd(OAc)2Cs2CO3 (1.2)DMSO140 °C/20 h-
10Pd(PPh3)4Cs2CO3 (1.2)DMSO140 °C/20 h74%
11 3Pd(OAc)2/PCy3·HBF4Cs2CO3 (1.2)DMSO140 °C/20 h-
12Pd(OAc)2/PCy3·HBF4Cs2CO3 (1.2)DMSO120 °C/20 h-
13Pd(OAc)2/PCy3·HBF4Cs2CO3 (1.2)toluene110 °C/20 h-
1 Reaction conditions: A mixture of 2aa (0.2 mmol), [Pd] (10 mol%), ligand (20 mol%) and base in solvent (2 mL) was heated in an oil bath under N2. 2 NMR yields. 3 Under air atmosphere.
Table 2. Spectral data of Dibenzofurotropones 1aa–1ga 1.
Table 2. Spectral data of Dibenzofurotropones 1aa–1ga 1.
Compd.λabs (nm) 2λmax (nm)λemi (nm)Δλstoke 3
1aa273 (20,002), 363 (11,677)36346299
1ab279 (26,170), 360 (17,098)360464104
1ac275 (19,714), 361 (11,859)36144786
1ad275 (29,226), 362 (15,367)36244886
1ae313 (26,321), 361 (14,403)36142564
1af274 (12,257), 371 (9087)371477106
1da278 (23,794), 358 (15,537)35843981
1ea273 (24,253), 374 (16,325)374486112
1fa282 (29,814), 359 (16,748)359464105
1ga282 (21,399), 368 (16,729)368473105
1 in EtOH (10 μM); 2 ε(M−1cm−1) given in parentheses; 3 Δλstokes = λemi − λmax, in nm.
Table 3. Spectral data of Dibenzofurotropones of 1ad in various solvents 1.
Table 3. Spectral data of Dibenzofurotropones of 1ad in various solvents 1.
Solventλabs (nm) 2λmax (nm)λemi (nm) Δλstoke 3
Toluene292 (14,833), 355 (14,988)35542671
THF296 (15,599), 351 (13,012)35139342
EtOAc276 (30,563), 351 (19,608)35139645
EtOH275 (29,226), 362 (15,367)36244886
CH3CN276 (28,451), 353 (17,793)35343380
1 10 μM in various solvents; 2 ε(M−1cm−1) given in parentheses; 3 Δλstokes = λemi − λmax, in nm.
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Lin, Y.-W.; Liu, S.-T. Preparation of Dibenzofurotropones via Pd-Catalyzed Cyclization. Reactions 2024, 5, 111-119. https://doi.org/10.3390/reactions5010005

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Lin Y-W, Liu S-T. Preparation of Dibenzofurotropones via Pd-Catalyzed Cyclization. Reactions. 2024; 5(1):111-119. https://doi.org/10.3390/reactions5010005

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Lin, Yu-Wei, and Shiuh-Tzung Liu. 2024. "Preparation of Dibenzofurotropones via Pd-Catalyzed Cyclization" Reactions 5, no. 1: 111-119. https://doi.org/10.3390/reactions5010005

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