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Article

Rapid Sequentially Palladium Catalyzed Four-Component Synthesis of Novel Fluorescent Biaryl-Substituted Isoxazoles

by
Tobias Deden
1,
Lars May
1,
Guido J. Reiss
2 and
Thomas J. J. Müller
1,*
1
Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany
2
Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany
*
Author to whom correspondence should be addressed.
Catalysts 2020, 10(12), 1412; https://doi.org/10.3390/catal10121412
Submission received: 5 November 2020 / Revised: 24 November 2020 / Accepted: 30 November 2020 / Published: 3 December 2020
(This article belongs to the Special Issue Catalysis in Heterocyclic and Organometallic Synthesis)
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Abstract

:
A series of novel 3- and 5-biaryl-substituted isoxazoles was prepared by a rapid microwave-assisted four-component three-step synthesis: concatenating Sonogashira coupling, cyclocondensation, and Suzuki coupling in a one-pot fashion. The Pd-catalyst was successfully employed in the sense of a sequentially catalyzed process, i.e., without the addition of further catalyst loading. Biaryl-substituted isoxazoles with donor–acceptor decoration possess remarkable photophysical properties, such as high fluorescence quantum yields in solution up to ΦF = 0.86 and large Stokes shifts up to 10,000 cm−1. The experimental absorption and emission characteristics can be reproduced and rationalized by computations on the DFT (density functional theory) and TDDFT (time-dependent density functional theory) level of theory.

Graphical Abstract

1. Introduction

Isoxazole, although scarcely found in nature, is an important aromatic heterocycle with considerable biological activity. For instance, isoxazole derivatives exhibit anti-inflammatory [1,2], anti-microbial [3,4], anti-viral [5], or anti-cancerogenic [6,7] profiles. Furthermore, isoxazoles are also found in neuropsychiatric therapy [8] and in crop protection [9]. Surprisingly, their photophysical properties have remained largely unexplored [10,11,12].
Isoxazole syntheses have been known for a long time, and various approaches to the formation of the isoxazole core can be found in the literature [13,14]. In the past decade alone, multicomponent reactions (MCR) of isoxazoles as one-pot accesses were reported for 3,5-disubstituted isoxazoles [15,16,17,18], 4-acyl-3,5-disubstituted isoxazoles [19], and 3,4,5-trisubstituted isoxazoles [20,21]. Surprisingly, isoxazoles with biphenyl substituents are scarcely found. Because of the biphenyl twist in the electronic ground state S0 (θ~34°), which transforms into coplanarity after photonic excitation and vibrational relaxation to S1, a favorable property of fluorescent chemosensors with large Stokes shifts can be derived [22,23,24]. Therefore, we envisioned an MCR approach to biaryl-substituted isoxazoles, enabling the design of functional π-systems based on diversity-oriented synthesis [25,26,27]. Inspired by our four-component synthesis of biaryl-substituted pyrazoles [28], we assumed that a sequentially Pd-catalyzed process can be transposed to the MCR formation of biarylated isoxazoles. Sequential catalysis is a particularly attractive concept, featuring multiple uses of an initially employed catalyst for a subsequent reaction step [29,30,31]. In line with the advantages of MCR, the catalyst is also used economically and effectively. Our retrosynthetic analysis of biaryl-substituted isoxazoles is based on the ynone approach [32], employing acid chloride and alkyne for ynone formation via Sonogashira coupling, followed by cyclocondensation with hydroxyl amine and concluded by Suzuki–Miyaura coupling in a one-pot fashion, i.e., a coupling–cyclocondensation–coupling (C3) sequence (Scheme 1).
Here, we report a novel sequentially Pd-catalyzed one-pot synthesis of biaryl-substituted isoxazoles in a consecutive four-component fashion. Furthermore, by a suitable donor–acceptor substitution enhancing the emission characteristics, the photonic properties are investigated by UV/vis and fluorescence spectroscopy, as well as by DFT (density functional theory) and TDDFT (time-dependent density functional theory) studies to rationalize the electronic structure.

2. Results and Discussion

2.1. Synthesis and Structure

Biaryl-substituted isoxazoles, as their pyrazole congeners [28], might be best accessible by catalytic ynone formation [32], with bromine containing aroyl chlorides or alkynes, setting two points of diversity in this type of level-two functionalization. The isoxazole core itself forms by regioselective Michael addition–cyclocondensation [18]. For the one-pot synthesis of 3-biaryl-substituted isoxazoles, we set out with a Pd-catalyzed Sonogashira coupling of an aroyl chloride 1 with p-bromophenyl acetylene (2a). After formation of the corresponding alkynone (monitored by TLC), the subsequent cyclocondensation with hydroxylamine was rapidly performed in the microwave reactor followed by Suzuki coupling of various boronic acids 3, without further addition of Pd catalysts to the reaction mixture (Scheme 2). The desired 3-biaryl-substituted isoxazoles 4 were isolated in moderate to very good yields for the overall reaction sequence of this four-component synthesis in less than 2 h (Table 1). The structures of compounds 4 were unambiguously assigned by 1H and 13C NMR spectroscopy and mass spectrometry.
Assuming that four new bonds are being formed in the sequence, the average yield per bond-forming step accounts for 65–95%. Aroyl chlorides with halogen substituents (Table 1, entries 3–5) or strongly electron donating and withdrawing boronic acids, such as 3d and 3f (Table 1, entries 8 and 10), give considerably lower yields after isolation by chromatography. However, in principle, both electron-rich (Table 1, entries 2, 6, 8) and electron-poor substituents (Table 1, entries 3–5, 7, 9) can be present on both aryl rings of the isoxazole. The introduction of an aldehyde functionality (Table 1, entry 9) opens up possibilities for further functionalization. A donor–acceptor conjugate with a methoxy and a nitrile substituent can be readily established (Table 1, entry 11).
For compound 4k, the molecular structure was additionally corroborated by single crystal structure analysis (Figure 1) [33]. The torsion angles θ of the four ring planes account for 13.2° for C(5)–C(4)–C(7)–C(8) (p-anisyl ring vs. isoxazole), −11.1° for C(8)–C(9)–C(10)–C(15) (isoxazole vs. central p-phenylene), and −4.8° for C(14)–C(13)–C(16)–C(21) (central p-phenylene vs. p-cyanophenyl) and indicate an almost coplanarily arranged geometry in the solid state.
The packing of isoxazole 4k was analyzed by a quantitative analysis of intermolecular interactions with Hirshfeld surfaces using the program CrystalExplorer [34] following a specific methodology [35,36,37]. The Hirshfeld surface (dnorm, Figure 2) displays close intermolecular contacts (red circles on the dnorm surface) from the nitrile nitrogen atom N2 to the hydrogen atom of C2 and the hydrogen atom of C18, as well as between the methoxy oxygen atom O2 and the methyl hydrogen atoms of C23. The majority of the surface is white or blue, representing the sum or longer than van-der-Waals contact distances, especially between molecules that are stacked side by side (Figure 2).
The synthesis of 5-biaryl-substituted isoxazoles was likewise performed employing p-bromobenzoyl chloride (1f) as a substrate (Scheme 3, Table 2). For this series, the yields after chromatography are considerably lower, and the targeted 5-biaryl-substituted isoxazoles 5 are obtained in 6–49% yield. However, three particularly photophysically interesting donor–acceptor decorated 5-biaryl-substituted isoxazoles were prepared (Table 2, entries 3–5). The structures of compounds 5 were unambiguously assigned by 1H and 13C NMR spectroscopy and mass spectrometry.
Most conveniently, the regioselectivity of isoxazoles is determined by EI (electron ionization) mass spectrometry as illustrated for the regioisomeric compounds 4a and 5a (Figure 3). Fragmentation of the isoxazole ring generally produces the corresponding acyl cation as a base fragment, displaying a high intensity in the EI mass spectrum. In comparison, fragment m/z = 105 is clearly detectable for compound 4a, while m/z = 195 is only found in the EI mass spectrum of regioisomer 5a.

2.2. Photophysical Properties

Compounds 4k, 5c, 5d, and 5e are distinctive push–pull systems and fluoresce strongly in solution already visible to the unaided eye. Therefore, the photophysical properties were thoroughly investigated by UV/vis and static fluorescence spectroscopy in solution (Figure 4, Table 3). Compound 4k is the only representative in this series bearing a biaryl substituent in 3-position and shows the most hypsochromically shifted absorption maximum at 294 nm with the highest molecular absorption coefficient ε (66,000 m−1 cm−1). The emission maximum of 4k appears at 423 nm, giving the largest Stokes shift in this series (10,400 cm−1). On the other hand, the fluorescence quantum yield ΦF = 0.17 is rather low. While the absorption maxima of compounds 5c and 5d are identical and appear at 311 nm (ε = 40,000 and 45,100 m−1 cm−1, resp.), compound 5e shows a large bathochromic shift to 356 nm (ε = 34,100 m−1 cm−1). The emission maximum of derivative 5d (411 nm) is bathochromically shifted in comparison to isoxazole 5c (376 nm), which implies the electronic influence of the stronger electron-withdrawing cyano substituent in comparison to the trifluoromethyl substituent. Beyond this, the introduction of the strong dimethylamino donor in compound 5e leads to a large bathochromic shift of the emission maximum to 554 nm. The resulting Stokes shifts for the consanguineous series of compounds 5c, 5d, and 5e are 5600, 7800 and 10,000 cm−1 and the fluorescence quantum yields are considerably high at ΦF = 0.86 (5c), ΦF = 0.62 (5d) and ΦF = 0.69 (5e).
In contrast to the strongest push-pull chromophore 5e, the biaryl-substituted isoxazoles 5c and 5d are reasonably soluble in solvents covering a broader polarity range. Measurements of the corresponding fluorescence maxima and relative emission intensity, in comparison to the intensity in toluene, reveal that the emission maxima redshift from toluene (5c: λmax,em = 373 nm, rel. intensity 1.00; 5d: λmax,em = 372 nm, rel. intensity 1.00) over dichloromethane (5c: λmax,em = 376 nm, rel. intensity 0.92; 5d: λmax,em = 411 nm, rel. intensity 0.25) to acetonitrile (5c: λmax,em = 407 nm, rel. intensity 0.59; 5d: λmax,em = 498 nm, rel. intensity 0.16) with concomitant attenuation of the emission intensity with increased polarity (for details, see Supplementary Materials, Table S3 (Solvent-dependent emission of compounds 5c and 5d (recorded at 293 K, c0(5) = 10−6 m, λexc = λmax,abs)), Figure S1 (Normalized emission spectra of 5c in toluene, CH2Cl2 and MeCN (recorded at 293 K, λexc = λmax,abs)) and Figure S2 (Normalized emission spectra of 5d in toluene, CH2Cl2 and MeCN (recorded at 293 K, λexc = λmax,abs))). Since specific interactions such as hydrogen bonding are absent, this steady diminution of fluorescence intensity with increasing redshift of the emission band is in full agreement with the energy gap law [40].
Compound 4k also shows fluorescence in a solid state that is visible to the unaided eye. Therefore, isoxazoles 4k, 5c, 5d and 5e were additionally investigated by solid-state fluorescence spectroscopy (Figure 5, Table 4). All compounds show measurable fluorescence, although the fluorescence quantum yields of 5c,d are only minor. The emission maxima follow the same trend as in solution with 5c showing the most blue-shifted emission at 391 nm, followed by 5d (405 nm), 4k (448 nm), and 5d with the most redshifted emission maximum at 508 nm.
Within the consanguineous series of isoxazoles 5c, 5d, and 5e, the photophysical properties generally follow the expected trend in accordance with the electronic nature of their substituents. However, the properties of isoxazole 4k clearly stand out. Compared to isomer 5d, changing the biphenyl positioning from the 5-position to the 3-position causes a hypsochromic shift of the absorption band, and a bathochromic shift of the emission band of compound 4k. Simultaneously, the fluorescence quantum yield drops from 0.62 (5d) to 0.17 (4k). Although different solvents were employed for determining the fluorescence quantum yield, further experiments clearly showed that the polarity of the solvent is not solely responsible for the differences in the quantum yields.

2.3. Computational Studies and Electronic Structure

A deeper understanding of the electronic structure of compounds 4k, 5c, 5d, and 5e was sought by DFT calculations using Gaussian09 [41]. The ground state geometries were optimized using the B3LYP functional [42,43,44,45,46] with the Pople 6-311G(d,p) basis set [47] applying the polarizable continuum model (PCM) [48] with dichloromethane as a solvent. The DFT optimized structures were confirmed as local minima by frequency analyses.
Based upon the crystal structure of compound 4k (vide supra), a closer look was taken at the conjugation of the π-electron system, comparing the computed torsion angles of isomers 4k and 5d in solution and of 4k in the solid state (Table 5). Expectedly, in solution angle γ of the biphenyl torsion of ~35° becomes apparent [49]. In the crystal structure of compound 4k, this torsional angle only amounts to 4.8°. The other torsional angles (around the isoxazole core) fall cum grano salis in the same margin. With regard to the crystal structure, it can be stated that the remarkably low biphenyl torsion angle in the crystal is probably a consequence of the observed packing effects.
Additionally, TD-DFT [50,51,52] calculations were employed to compute the absorption maxima for these compounds (CAM-B3LYP functional [53]; 6-311++G(d,p) basis set; PCM: dichloromethane). In general, the computed values for the absorption maxima are in good agreement with the experiment (Table 6). Only derivative 5e shows an even stronger bathochromic shift in the absorption maximum (356 nm) than predicted by the calculation (333 nm).
According to TD-DFT calculations, the longest wavelength absorption bands of compounds 5c, 5d, and 5e, possess dominant contributions of HOMO→LUMO and HOMO→LUMO+1 transitions. It is noteworthy that compound 4k does not involve the HOMO→LUMO transition as a constituent of the longest wavelength absorption band. The calculated electronic structure reveals that the longest wavelength absorption band consists of dominant contributions of HOMO-1→LUMO and HOMO→LUMO+1 transitions, which both reveal local excitation character at higher energies in the p-cyano biphenyl oxazole part (HOMO-1→LUMO) and in the p-anisyl isoxazole moiety (HOMO→LUMO+1) (Figure 6, left). The relative contribution of the HOMO→LUMO transition decreases gradually from 5c to 5e, possibly caused by diminished orbital overlap due to increasing charge-transfer character. With increasing acceptor strength, the amount of the HOMO→LUMO+1, representing charge transfer transition over the complete molecule, steadily increases. The HOMO→LUMO, also charge transfer in its nature, only possesses a moderate overlap in the central isoxazole. Expectedly, stronger acceptor substituents attenuate the central overlap on the isoxazole, and, consequently, the HOMO→LUMO+1 transition prevails (Figure 6, right).
This behavior can be additionally quantified by coefficient density analysis of the corresponding DFT data for ground state optimization using Multiwfn (Table 7) [54]. The distance between coefficient density focal points of HOMO and LUMO, dFMO, increases from structure 5c to 5d, while the overlap integral of HOMO and LUMO, <HOMO|LUMO>, gradually decreases. The distinct charge transfer character of 5e in comparison to 5c can be illustrated by HOMO–LUMO difference plots (Figure 7).
A conclusion from the study of the electronic structures is that the 5-biaryl-substituted isoxazoles 5 are better suited for fine-tuning of the absorption and emission properties over a broad part of the spectrum. With the highly emissive compound 5c as a model system, the optimized geometry of the vibrationally relaxed excited state (S1) was calculated with Gaussian09, employing the same functional and basis set as for ground state optimization in dichloromethane. Via TD-DFT, the emission from S1 to the Franck–Condon state S0FC2 was calculated. In addition to the optimization of S0 and excitation to S1FC1, the whole excitation–emission cycle of 5c could be computationally simulated (Figure 8). The computed emission maximum λmax,em,DFT = 361 nm is in good agreement with the experiment (λmax,em,exp = 376 nm). It is noticeable that the geometry of the S1 is essentially planarized compared to the equilibrium geometry of S0.

3. Conclusions

A concise consecutive four-component synthesis of novel biaryl-substituted isoxazoles was successfully established. Interestingly, the palladium catalyst can be employed sequentially for both Sonogashira coupling and Suzuki coupling without addition of further catalyst. The one-pot process is intercepted by a regioselective cyclocondensation of the initially formed alkynone with hydroxyl amine. Selected derivatives with a donor–acceptor substitution pattern display pronounced fluorescence in solution and remarkably high relative fluorescence quantum yields in most cases, a property which has been scarcely described for isoxazoles. In a consanguineous series of 5-biaryl-substituted isoxazoles with increasing donor and acceptor strengths, the tunability of Stokes shift between 5600 to 10,000 cm−1 (sic!) can be impressively shown. The same compounds are also emissive in the solid state, though with rather low fluorescence quantum yields. Quantum chemical calculations plausibly rationalize the electronic properties in good agreement with the experimental results. These novel biaryl-substituted isoxazoles are intensively emissive in nonpolar environments and are therefore perfectly suited for developing lipophilic luminophores for biophysical application. Studies to incorporate biaryl oxazole luminophores into polystyrene particles and ligating them to biologically interesting lipophilic targets, such as bilayer membranes, are currently underway.

Supplementary Materials

The following are available online at https://www.mdpi.com/2073-4344/10/12/1412/s1, Figure S1: Normalized emission spectra of 5c in toluene, CH2Cl2 and MeCN (recorded at 293 K, λexc = λmax,abs), Figure S2: Normalized emission spectra of 5d in toluene, CH2Cl2 and MeCN (recorded at 293 K, λexc = λmax,abs), Figure S3: Asymmetric unit of isoxazole 4k (thermal ellipsoids shown at 50% probability), Figure S4: Hirshfeld surface of isoxazole 4k in the crystal lattice mapped with the dnorm´property. Red represents the closest, blue the most distant contacts, Figure S5: Optimized ground state geometry of 4k (B3LYP/6-311G(d,p), PCM CH2Cl2), Figure S6: Optimized ground state geometry of 5c (B3LYP/6-311G(d,p), PCM CH2Cl2), Figure S7: Optimized S1 geometry of 5c (B3LYP/6-311G(d,p), PCM CH2Cl2), Figure S8: Optimized ground state geometry of 5c (B3LYP/6-311G(d,p), PCM CH2Cl2), Figure S9: Optimized ground state geometry of 5e (B3LYP/6-311G(d,p), PCM CH2Cl2), Table S1: Experimental details for the synthesis of 3-biarylsubstituted isoxazoles, Table S2. Experimental details for the synthesis of 5-biarylsubstituted isoxazoles, Table S3: Solvent-dependent emission of compounds 5c and 5d (recorded at 293 K, c0(5) = 10− 6 m, λexc = λmax,abs). General information on the experimental procedures and analytics; general procedures for the one-pot syntheses and analytical data of 3-biaryl-substituted isoxazoles 4 and 5-biaryl-substituted isoxazoles 5, 1H and 13C NMR spectra of compounds 4 and 5, crystal data and structure refinement for compound 4k, data of quantum chemical calculations on selected structures 4l, 5c, 5d, and 5e.

Author Contributions

The work is part of the Ph. D. thesis of T.D., which was supervised by T.J.J.M. The conceptualization was outlined and accompanied by T.J.J.M. Synthetic studies, analytical assignments, and photophysical investigations were performed by T.D., who compiled and interpreted the obtained data. Quantum chemical calculations were performed by L.M. and T.D., and the crystal structure analysis was carried out and interpreted by G.J.R. Writing of the original draft was done by T.D., and review and editing by T.J.J.M. Project administration and funding acquisition was conducted by T.J.J.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Jürgen-Manchot-Stiftung Düsseldorf (scholarship for T.D.), and by Fonds der Chemischen Industrie (scholarship for L.M. and ad personam support for T.J.J.M.).

Acknowledgments

The authors cordially thank the Jürgen-Manchot-Stiftung Düsseldorf and Fonds der Chemischen Industrie for financial support. Computational infrastructure and support were provided by the Centre for Information and Media Technology at Heinrich Heine University Düsseldorf.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

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Catalysts 10 01412 sch001 550
Scheme 1. Retrosynthetic analysis of biaryl-substituted isoxazoles via coupling–cyclocondensation–coupling (C3) one-pot methodology including sequential use of the Pd catalyst.
Scheme 1. Retrosynthetic analysis of biaryl-substituted isoxazoles via coupling–cyclocondensation–coupling (C3) one-pot methodology including sequential use of the Pd catalyst.
Catalysts 10 01412 sch001
Catalysts 10 01412 sch002 550
Scheme 2. Consecutive coupling–condensation–coupling (C3) synthesis of 3-biaryl-substituted isoxazoles 4.
Scheme 2. Consecutive coupling–condensation–coupling (C3) synthesis of 3-biaryl-substituted isoxazoles 4.
Catalysts 10 01412 sch002
Catalysts 10 01412 g001 550
Figure 1. Molecular structure of compound 4k (thermal ellipsoids shown at 50% probability).
Figure 1. Molecular structure of compound 4k (thermal ellipsoids shown at 50% probability).
Catalysts 10 01412 g001
Catalysts 10 01412 g002 550
Figure 2. Hirshfeld surface of isoxazole 4k in the crystal lattice mapped with the dnorm property [37]. Red represents the closest, blue the most distant contacts.
Figure 2. Hirshfeld surface of isoxazole 4k in the crystal lattice mapped with the dnorm property [37]. Red represents the closest, blue the most distant contacts.
Catalysts 10 01412 g002
Catalysts 10 01412 sch003 550
Scheme 3. Consecutive coupling–condensation–coupling (C3) synthesis of 5-biaryl-substituted isoxazoles 5.
Scheme 3. Consecutive coupling–condensation–coupling (C3) synthesis of 5-biaryl-substituted isoxazoles 5.
Catalysts 10 01412 sch003
Catalysts 10 01412 g003 550
Figure 3. Determination of regioisomers by EI (electron ionization) mass spectrometry (relative intensity in parentheses).
Figure 3. Determination of regioisomers by EI (electron ionization) mass spectrometry (relative intensity in parentheses).
Catalysts 10 01412 g003
Catalysts 10 01412 g004 550
Figure 4. Normalized absorption (solid line) and emission (dashed line) spectra of biaryl-substituted isoxazoles 4k, 5c, 5d, and 5e (recorded in CH2Cl2 at 293 K, λexc = λmax,abs).
Figure 4. Normalized absorption (solid line) and emission (dashed line) spectra of biaryl-substituted isoxazoles 4k, 5c, 5d, and 5e (recorded in CH2Cl2 at 293 K, λexc = λmax,abs).
Catalysts 10 01412 g004
Catalysts 10 01412 g005 550
Figure 5. Normalized solid-state emission spectra of biaryl-substituted isoxazoles 4k, 5c, 5d, and 5e (λexc = 300 or 330 nm, recorded at 293 K).
Figure 5. Normalized solid-state emission spectra of biaryl-substituted isoxazoles 4k, 5c, 5d, and 5e (λexc = 300 or 330 nm, recorded at 293 K).
Catalysts 10 01412 g005
Catalysts 10 01412 g006 550
Figure 6. Comparison of selected DFT-computed Kohn–Sham frontier molecular orbitals and corresponding orbital energies between compounds 4k (left) and 5d (right) (B3LYP/6-311G(d,p); PCM: CH2Cl2).
Figure 6. Comparison of selected DFT-computed Kohn–Sham frontier molecular orbitals and corresponding orbital energies between compounds 4k (left) and 5d (right) (B3LYP/6-311G(d,p); PCM: CH2Cl2).
Catalysts 10 01412 g006
Catalysts 10 01412 g007 550
Figure 7. Comparison of HOMO–LUMO difference plots between isoxazoles 5c (left) and 5e (right).
Figure 7. Comparison of HOMO–LUMO difference plots between isoxazoles 5c (left) and 5e (right).
Catalysts 10 01412 g007
Catalysts 10 01412 g008 550
Figure 8. Computed results for excitation to the Franck–Condon state S1FC1, vibrational relaxation to S1, emission to Franck–Condon state S0FC2 and relaxation to S0 of compound 5c. Geometry optimization of S0/S1: B3LYP/6-311G(d,p), PCM: CH2Cl2; absorption/emission: CAM-B3LYP/6-311++G(d,p); PCM: CH2Cl2.
Figure 8. Computed results for excitation to the Franck–Condon state S1FC1, vibrational relaxation to S1, emission to Franck–Condon state S0FC2 and relaxation to S0 of compound 5c. Geometry optimization of S0/S1: B3LYP/6-311G(d,p), PCM: CH2Cl2; absorption/emission: CAM-B3LYP/6-311++G(d,p); PCM: CH2Cl2.
Catalysts 10 01412 g008
Table
Table 1. 3-Biaryl-substituted isoxazoles 4 by four-component coupling–condensation–coupling (C3) synthesis.
Table 1. 3-Biaryl-substituted isoxazoles 4 by four-component coupling–condensation–coupling (C3) synthesis.
EntryAcid Chloride 1Boronic Acid 33-Biaryl-substituted Isoxazoles 4
1R1 = Ph (1a)R3 = p-MeC6H4 (3a) Catalysts 10 01412 i0014a (80%)
2R1 = p-MeOC6H4 (1b)3a Catalysts 10 01412 i0024b (66%)
3R1 = o-FC6H4 (1c)3a Catalysts 10 01412 i0034c (36%)
4R1 = p-F3CC6H4 (1d)3a Catalysts 10 01412 i0044d (25%)
5R1 = m-ClC6H4 (1e)3a Catalysts 10 01412 i0054e (26%)
61aR3 = p-MeOC6H4 (3b) Catalysts 10 01412 i0064f (74%)
71aR3 = p-NCC6H4 (3c) Catalysts 10 01412 i0074g (71%)
81aR3 = p-Me2NC6H4 (3d) Catalysts 10 01412 i0084h (27%)
91aR3 = p-OHCC6H4 (3e) Catalysts 10 01412 i0094i (53%)
101aR3 = p-O2NC6H4 (3f) Catalysts 10 01412 i0104j (18%)
111b3c Catalysts 10 01412 i0114k (51%)
Table
Table 2. 5-Biaryl-substituted isoxazoles 5 by four-component coupling–condensation–coupling (C3) synthesis.
Table 2. 5-Biaryl-substituted isoxazoles 5 by four-component coupling–condensation–coupling (C3) synthesis.
EntryAlkyne 2Boronic Acid 35-Biaryl-substituted Isoxazoles 5
1R2 = Ph (2b)R3 = p-MeC6H4 (3a) Catalysts 10 01412 i0125a (49%)
22bR3 = p-MeOC6H4 (3b) Catalysts 10 01412 i0135b (29%)
3R2 = p-F3CC6H4 (2c)3b Catalysts 10 01412 i0145c (13%)
4R2 = p-NCC6H4 (2d)3b Catalysts 10 01412 i0155d (6%)
52dR3 = p-Me2NC6H4 (3d) Catalysts 10 01412 i0165e (34%)
Table
Table 3. Selected photophysical properties of biaryl-substituted isoxazoles 4k, 5c, 5d, and 5e (recorded in CH2Cl2 at 293 K).
Table 3. Selected photophysical properties of biaryl-substituted isoxazoles 4k, 5c, 5d, and 5e (recorded in CH2Cl2 at 293 K).
CompoundAbsorption Maxima λmax,abs (nm) (ε (M−1 cm−1))Emission Maxima λmax,em (nm) (ΦF)Stokes Shift a Δ ν ˜ (cm−1)
4k294 (66,000)423 (0.17) b10,400
5c311 (40,000)376 (0.86) b5600
5d311 (45,100)411 (0.62) b7800
5e356 (34,100)554 (0.69) c10,000
a Stokes shift Δ ν ˜ = 1/λmax,abs – 1/λmax,em (cm−1). b Quantum yield ΦF was determined in toluene (4k), CH2Cl2 (5c) or THF (tetrahydrofuran) (5d) with 2,5-diphenyloxazole as a standard in methanol (ΦF = 0.86) [38], λexc = 280 nm. c Quantum yield ΦF was determined in toluene with coumarin 1 as a standard in ethanol (ΦF = 0.73) [39], λexc = 373 nm.
Table
Table 4. Solid-state emission maxima of 4k, 5c, 5d, and 5e (recorded at 293 K).
Table 4. Solid-state emission maxima of 4k, 5c, 5d, and 5e (recorded at 293 K).
CompoundEmission Maxima λmax,em (nm) (ΦF)
4k448 (0.07) a
5c391 (<0.01) a
5d405 (<0.01) a
5e508 (<0.01) b
aλexc = 300 nm, b λexc = 330 nm.
Table
Table 5. Comparison of computed torsion angles between isoxazoles 4k and 5d (B3LYP/6-311G(d,p); polarizable continuum model (PCM): CH2Cl2).
Table 5. Comparison of computed torsion angles between isoxazoles 4k and 5d (B3LYP/6-311G(d,p); polarizable continuum model (PCM): CH2Cl2).
CompoundTorsional Angle αTorsional Angle β Torsional Angle γ
Catalysts 10 01412 i0174k0.5°12.8°36.3°
Catalysts 10 01412 i0185d0.1°9.0°34.8°
Table
Table 6. Experimental (recorded in CH2Cl2 at 293 K) and TDDFT (time-dependent density functional theory) calculated of the absorption maxima of isoxazoles 4k, 5c, 5d, and 5e (CAM-B3LYP/6-311++G(d,p); PCM: CH2Cl2).
Table 6. Experimental (recorded in CH2Cl2 at 293 K) and TDDFT (time-dependent density functional theory) calculated of the absorption maxima of isoxazoles 4k, 5c, 5d, and 5e (CAM-B3LYP/6-311++G(d,p); PCM: CH2Cl2).
CompoundExperimental λmax,abs (nm) (ε (m−1 cm−1))Calculated λmax,abs (nm) (Oscillatory Strength) Most Dominant Contributions
4k294 (66,000)285 (2.187)HOMO-1→LUMO (65%) HOMO→LUMO+1 (27%)
5c311 (40,000)302 (1.436)HOMO→LUMO (67%) HOMO→LUMO+1 (20%)
5d311 (45,100)303 (1.496)HOMO→LUMO (37%) HOMO→LUMO+1 (50%)
5e356 (34,100)333 (2.187)HOMO→LUMO (30%) HOMO→LUMO+1 (54%)
Table
Table 7. Coefficient density analysis of 5c–e carried out with Multiwfn [54].
Table 7. Coefficient density analysis of 5c–e carried out with Multiwfn [54].
CompounddFMO (Å)<HOMO|LUMO>HOMO→LUMO (%)
5c6.1430.54167
5d9.0050.33837
5e11.1360.22130
Sample Availability: Samples of the compounds 4f, 4g, and 5e are available from the authors.
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Deden, T.; May, L.; Reiss, G.J.; Müller, T.J.J. Rapid Sequentially Palladium Catalyzed Four-Component Synthesis of Novel Fluorescent Biaryl-Substituted Isoxazoles. Catalysts 2020, 10, 1412. https://doi.org/10.3390/catal10121412

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Deden T, May L, Reiss GJ, Müller TJJ. Rapid Sequentially Palladium Catalyzed Four-Component Synthesis of Novel Fluorescent Biaryl-Substituted Isoxazoles. Catalysts. 2020; 10(12):1412. https://doi.org/10.3390/catal10121412

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Deden, Tobias, Lars May, Guido J. Reiss, and Thomas J. J. Müller. 2020. "Rapid Sequentially Palladium Catalyzed Four-Component Synthesis of Novel Fluorescent Biaryl-Substituted Isoxazoles" Catalysts 10, no. 12: 1412. https://doi.org/10.3390/catal10121412

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