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DOI: 10.1055/a-2193-4701
Copper Nanoparticles on Montmorillonite K-10: A Versatile Catalyst for the One-Pot Synthesis of 3,5-Disubstituted Isoxazoles Using Various Methodologies
This work was generously supported by the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, PIP-2021-2023-1665), Fondo para la Investigación Científica y Tecnológica, Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT, Prest. BID PICT-2018-2471), and Secretaría General de Ciencia y Tecnología, Universidad Nacional del Sur (UNS, PGI 24/Q106) from Argentina. S.S. thanks CONICET for a postdoctoral fellowship and E.E.B. thanks CONICET for a doctoral fellowship.
Abstract
A readily prepared and versatile heterogeneous catalyst composed of copper nanoparticles supported on montmorillonite K-10 (CuNPs/MK-10) has proven to be highly effective in catalyzing the synthesis of isoxazoles through various one-pot methodologies with high atom economy. These methodologies allow for the use of readily available starting materials, including aldehydes and alkynes through 1,3-dipolar cycloaddition reactions, as well as via cycloisomerization of ynones. Additionally, the CuNPs/MK-10 catalyst promoted the in situ formation of the ynones via an acyl Sonogashira coupling. Furthermore, a three-step one-pot methodology was also developed, starting from carboxylic acids and involving the in situ generation of acyl chlorides.
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Key words
isoxazole synthesis - copper nanoparticles - heterogeneous catalysis - 1,3-dipolar cycloaddition - cycloisomerizationHeterocyclic compounds hold a prominent position among natural and synthetic organic structures of relevance to medicinal chemistry due to their wide spectrum of biological activities. Particularly, nitrogen- and oxygen-based heterocyclic motifs are ubiquitous across the most active pharmacophores.[1] Among them, isoxazoles are privileged structures containing a five-membered heteroaromatic ring with nitrogen and oxygen atoms connected to each other. This 1,2-relationship of two electronegative atoms provides the isoxazole with the unique ability to interact with enzymes and bioreceptors through hydrogen-bond donor–acceptor interactions. In fact, the isoxazole motif ranks in the first decile among more than 350 ring systems found in pharmaceutical marketed drugs (Figure [1]).[2]
On the other hand, isoxazoles are synthetic equivalents of a variety of valuable organic functionalities. Despite the aromatic character of isoxazoles, the weakness of the N–O bond makes them useful intermediates as masked γ-amino alcohols, β-hydroxy nitriles and 1,3-dicarbonyl compounds, among others.[3] [4] Consequently, the broad range of applications as both bioactive compounds and versatile synthetic intermediates has sparked ongoing interest in developing new methodologies to access these five-membered N,O-heterocycles. As a result, in the last decade a large number of metal-promoted and metal-free synthetic methods for the construction and functionalization of isoxazoles have been published and summarized in various outstanding comprehensive review articles.[3a] , [4–6]
The isoxazole ring can be accessed through various synthetic strategies (Figure [2]), with the 1,3-dipolar cycloaddition between alkynes and nitrile oxides being the most commonly employed route.[7a] Other frequently used methods for constructing the isoxazole ring include condensation of hydroxylamine with 1,3-diketones or α,β-unsaturated ketones,[7b] cycloisomerization of ynone oximes[7c] and direct functionalization of isoxazoles.[7d]
1,3-Dipolar cycloaddition reactions are of particular interest to our research group. In our labs, and in cooperation with Alonso’s group,[8] we have deeply studied cycloaddition reactions catalyzed by copper nanoparticles (CuNPs) for the click synthesis of 1,2,3-triazoles (CuAAC), including some bioactive derivatives.[9] The paradigmatic status of this transformation in synthetic organic chemistry has been recognized with the 2022 Nobel Prize Award granted to Sharpless, Meldal and Bertozzi for their pivotal contributions in this area.[10]
The exponential advances around the CuAAC reaction over the last decades prompted chemists to further explore the use of dipoles beyond azides in cycloaddition processes. Specifically, there has been a growing interest in employing nitrile oxides as dipoles and alkynes as dipolarophiles for the synthesis of isoxazoles.[7a] Even when most cycloadditions between nitrile oxides and alkynes proceed under thermal conditions, the pioneering works by Fokin and co-workers demonstrated that ruthenium- or copper-based catalysts allow the synthesis of 3,4- and 3,5-disubstituted isoxazoles with almost complete regioselectivity.[11] These findings have fostered the development of several homogeneous transition-metal-catalyzed [3+2]-cycloaddition approaches for the regioselective synthesis of isoxazoles,[6] [12] while the application of heterogeneous catalysis for this transformation remained scarcely studied.[13]
The use of heterogeneous catalytic systems, although in some cases less active and/or selective than their homogeneous counterparts, is attractive since the catalyst can be recovered from the reaction mixture for its reuse. This is particularly significant for industrial applications and the synthesis of bioactive products of pharmaceutical interest, where any metal traces must be avoided.[14]
On the other hand, in modern organic synthesis there is a continued demand for operationally simple and atom-economic methodologies. In this context, one-pot procedures, either multicomponent or sequential, that minimize time-consuming purification procedures and harmful waste generation, are preferred over multistep processes. Regarding the synthesis of isoxazoles by metal-catalyzed [3+2]-cycloaddition reactions, one-pot methodologies are not abundant in the scientific literature, even though the in situ generation of unstable nitrile oxides is crucial for minimizing the dimerization of these dipoles.[15] An innovative one-pot strategy was developed by Fokin and co-workers, starting from aldehydes. The aldehydes were converted in situ into the corresponding aldoximes, which were then reacted with chloramine-T to form the corresponding nitrile oxides. Subsequent addition of the alkyne and a Cu(I) catalyst, obtained from comproportionation of Cu metal and CuSO4, enabled the one-pot synthesis of 3,5-disubstituted isoxazoles with excellent regioselectivity.[11a] In a recent work, Zhang, Hu and co-workers presented an attractive one-pot strategy starting from amines and alkynes catalyzed by [Cp*RhCl2]2. Amines were selectively oxidized with tert-butyl nitrite to render the corresponding nitrile oxides which, after cycloaddition with the starting alkyne, gave 3,5-disubstituted isoxazoles regiospecifically.[16] Other one-pot methods for constructing isoxazole rings through transition-metal-catalyzed [3+2] cycloaddition require the use of pre-synthesized nitrile oxide precursors, such as hydroximoyl halides, alkylazaarenes or diazo compounds, as starting materials, making these procedures less synthetically attractive.[11b] [12b] [d] [17]
It is worth noting that a preliminary literature survey reveals that one-pot methodologies involving heterogeneous transition-metal catalysis for this transformation have remained virtually unexplored. Prompted by our interest in this area, we present herein our work on the one-pot synthesis of 3,5-disubstituted isoxazoles from readily available starting materials. The process is promoted by an inexpensive and easy-to-prepare heterogeneous copper-based catalyst consisting of copper nanoparticles supported on montmorillonite K-10 (CuNPs/MK-10). The reaction can be carried out under either microwave irradiation or thermal heating.
We started our study by optimizing the reaction conditions for the one-pot sequential cycloaddition between benzaldehyde as the precursor for the in situ generation of the corresponding nitrile oxide, and phenylacetylene as the dipolarophile. As it is known, regioselectivity control of this [3+2] cycloaddition could be strongly influenced by the choice and combination between the metal catalyst and the reaction partners, so a series of freshly prepared CuNPs-based nanocatalysts, consisting of CuNPs immobilized on different supports, were screened during the optimization of the reaction conditions. As previously reported by some of us, the copper nanocatalysts were readily prepared by adding the support to a suspension of freshly synthesized copper nanoparticles. These CuNPs were obtained through fast reduction of anhydrous copper(II) chloride at room temperature, using lithium sand and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 10 mol%) as the reducing system, in THF. After filtration and drying, the catalysts were ready for immediate utilization.[18]
The reaction starts with the conversion of the aldehyde into the corresponding aldoxime by treatment with hydroxylamine hydrochloride and then transformation into the corresponding nitrile oxide by reaction with chloramine-T trihydrate. The in situ generated nitrile oxide was reacted with phenylacetylene, in the presence of the copper nanocatalyst, using water as green solvent (Table [1]).
It is important to note that the reactions were tested both under conventional heating or microwave irradiation. As shown in Table [1], CuNPs immobilized on montmorillonite K-10 (CuNPs/MK-10, entry 7) proved to be the best catalyst for this transformation. The preparation and characterization of this catalyst (see experimental and Supporting Information) have been previously reported by some of us elsewhere.[19] The CuNPs/MK-10 catalyst consists of spherical CuNPs with a diameter of ca. 2.5 ± 1.5 nm (TEM, Supporting Information), highly dispersed on the support, and with a copper content of 1.7 wt % as determined by AAS and ICP/MS. Interestingly, microwave irradiation (60 W/100 °C) allowed us to obtain the corresponding 3,5-disubstituted isoxazole product with a higher yield and significantly shorter reaction time than that observed when using conventional heating, with complete regioselectivity (compare entries 1 and 11, 2 and 12, 7 and 14, 9 and 13). Further variations in microwave power, catalyst loading or temperature did not improve the reaction yield (Table [1], entries 15–19). A reaction carried out in the absence of the copper catalyst resulted in a lower conversion of the starting alkyne (55%) into a mixture of both possible regioisomers, the 3,5-disubstituted isoxazole being the major product (6:1 ratio).
During the optimization of reaction conditions, it was observed that the product yields were highly dependent on the procedure employed for the in situ generation of the nitrile oxide. Specifically, it was found that the process was too sensitive to the manner in which chloramine-T was added to the reaction mixture, either in small portions over long periods of time or at low temperatures (ice bath). Since the use of chloramine-T was not so straightforward as usually described in the literature, showing also some inconveniences in its reproducibility, we decided to explore an alternative synthetic route involving N-hydroxyimidoyl chlorides as precursors of the nitrile oxide intermediates. Based on the results reported by Chanda and co-workers,[12a] we studied the one-pot synthesis of isoxazole 5a in a telescopic manner, via one-pot sequential addition of NCS to the aldoxime, followed by the alkyne and the CuNPs/MK-10 catalyst, thus enabling the in situ generation of the corresponding N-hydroxyimidoyl chloride as the nitrile oxide precursor. The reaction in DMF proceeded smoothly, leading to 5a in excellent yield and with complete regioselectivity (Table [1], entry 20). Additionally, by using this methodology, all the reaction steps could be carried out under microwave irradiation, which is an advantage from a practical point of view. Unfortunately, when the same process was carried out in water as the solvent, a significantly lower conversion of the starting alkyne was observed (52%). Finally, when the reaction was carried out in the presence of the support (MK-10) alone, using either chloramine-T (method A) or NCS (method B) for the nitrile oxide formation, lower yields and regioselectivities were obtained compared to those achieved with the CuNPs/MK-10 catalyst (Table [1], entries 21 and 22).
a Starting reaction conditions: i) benzaldehyde (53 mg, 0.5 mmol), NH2OH·HCl (38 mg, 0.55 mmol, 1.1 equiv), H2O (2 mL), rt, 30–60 min; ii) TsN(Cl)Na·3H2O (148 mg, 0.53 mmol, 1.05 equiv); iii) phenylacetylene (51 mg, 0.5 mmol), CuNPs catalyst (20 mg, 1.0 mol% Cu), 100 °C under conventional heating or MW irradiation.
b Isolated yield after flash column chromatography (silica gel, hexane/EtOAc).
c The corresponding N-hydroxyimidoyl chloride was formed by reaction of the aldoxime with NCS in DMF (2 mL).
d 3,5-Disubstituted isoxazole as the major product (20:1 ratio).
e 3,5-Disubstituted isoxazole as the major product (25:1 ratio).
We then tested the scope of our methodology by using a range of aldehydes and alkynes as starting substrates. In situ generation of the corresponding nitrile oxide intermediates was performed through the reaction with either chloramine-T (method A) or NCS (method B), as depicted in Scheme [1].
We started our study by reacting benzaldehyde with alkynes of different nature. As shown in Figure [3], phenylacetylene or substituted phenylacetylenes, with the exception of compound 5d, were unaffected by the method employed for the generation of the corresponding intermediates. On the other hand, method B was found to be more efficient for the synthesis of isoxazoles derived from all the other alkynes tested, including an aliphatic one (5e) and enyne (5f). Furthermore, this method exhibited greater compatibility with the presence of other functional groups in the starting alkyne, such as propargyl ether (5g, 5h), propargyl alcohol (5i) and 2-pyridyl group (5j). Additionally, when method A was employed, no conversion into products 5i and 5j was observed, although at this stage we have not found a clear explanation for this. It is worthy of note the result obtained when a diyne was used as starting alkyne (5k), as no formation of the corresponding bis-isoxazole product was observed. Despite the moderate conversion into 5k, the high selectivity observed would enable further functionalization of the remaining carbon–carbon triple bond. For instance, it could be reacted with a similar or different dipole, such as another nitrile oxide or an organic azide.
In light of these results, and considering the greater simplicity and operational practicality of method B, we decided to employ this methodology to carry out a reactivity screening of a variety of aldehydes with phenylacetylene as the starting alkyne. As shown in Figure [4], various substituted benzaldehydes and naphthaldehyde led to the corresponding 3,5-disubstituted isoxazoles in good to excellent yields (5l–q). In contrast, aliphatic aldehydes exhibited poor reactivity (5r, 5s), possibly due to the lower stability of the corresponding reaction intermediates.[20] Furthermore, they have rarely been reported in the scientific literature as starting materials for this transformation.
To our delight, vanillin reacted smoothly, yielding isoxazoles 5u–w without the need to protect the hydroxyl group (Figure [4]). To the best of our knowledge, there are no reports of direct metal-catalyzed [3+2] cycloadditions using this type of substrate, bearing a free hydroxyl group.
After completing the screening of aldehydes and alkynes, we decided to study the catalyst reuse. For that, we utilized benzaldehyde and phenylacetylene as starting compounds and carried out the synthesis of the corresponding isoxazole 5a using the optimal conditions for the above-described method B. Once the first reaction cycle was completed, the CuNPs/MK-10 catalyst was easily recovered from the reaction mixture through centrifugation, followed by sequential washing with water (3 × 1 mL) and EtOAc (3 × 1 mL). Then, the catalyst was dried under vacuum and reused without any other treatment. By following this procedure, the CuNPs/MK-10 catalyst could be reutilized in four consecutive cycles without apparent loss of activity, exhibiting very good conversions towards the 3,5-disubstituted isoxazole 5a (90%, 86%, 86%, 87%).
As mentioned in the introductory text, cycloisomerization reactions provide another valuable approach to access the isoxazole ring. Metal-catalyzed cycloisomerizations for the synthesis of isoxazoles offer significant advantages, including milder reaction conditions and compatibility with a wide range of functional groups. Several homogeneous metal catalysts have been reported for this transformation, commonly utilizing Au, Ag, Pd and Pt salts or complexes, while Cu-based catalysts have received comparatively less attention.[1g] [21] Typically, these metal-catalyzed methods have been utilized for the synthesis of 3,4,5-trisubstituted isoxazoles. On the other hand, in most cases the corresponding oximes usually demand O-substitution, such as O-methylation or O-benzylation, which entails the use of alkynyl oxime ethers as starting materials. Miyata and co-workers reported the use of Cu(OTf)2 and O-benzyl alkynyl oximes to synthesize isoxazoles via cycloisomerization/benzyl 1,3-migration.[22] Another interesting method has been reported by Song, Zhu and co-workers, consisting of the one-pot oxidation/cyclization of propargylamines catalyzed by CuCl.[23] According to the proposed mechanism, oxidation of the propargylamines would yield the corresponding oximes, which subsequently undergo Cu(I)-mediated cyclization to give the desired isoxazoles.
Taking into account the synthetic potential of utilizing ynone oximes for isoxazole synthesis, we decided to further explore the performance and versatility of the CuNPs/MK-10 catalyst in the cycloisomerization of this kind of starting substrate. As a first approach, we studied a one-pot procedure starting from ynone 6l, and the in situ formation of the corresponding ynone oxime followed by cyclization promoted by the CuNPs/MK-10 catalyst. The optimization of the reaction conditions is shown in Table [2].
a Reaction conditions: ynone 6l (59 mg, 0.25 mmol), NH2OH·HCl, NaHCO3, catalyst, H2O/DMF (1:1, 2 mL), heated at 120 °C in a sealed tube overnight.
b Yields were determined by 1H NMR spectroscopy.
c Under MW irradiation (60 W, 120 °C).
d Reaction performed without CuNPs, only in the presence of the MK-10 support.
As can be seen from the results in Table [2], when using the same catalyst loading (1.0 mol% Cu) as in the above-described methodologies for the nitrile oxide–alkyne cycloadditions (Scheme [1]), isoxazole 5l was obtained in 48% yield (Table [2], entry 1). Increasing the excess of hydroxylamine slightly improved the reaction yield up to 55% (Table [2], entry 2). Next, the catalyst loading was doubled, resulting in a significantly increased yield of 75% (Table [2], entry 3). However, tripling the amount of catalyst resulted in a yield drop to 40% (Table [2], entry 4), indicating the high sensitivity of the process to the optimal catalyst loading. With regard to the reaction temperature, increasing it from 100 °C to 120 °C resulted in the formation of the desired isoxazole with an excellent yield of 90% (Table [2], entry 5). In an attempt to reduce the reaction time, the process was conducted using microwave irradiation (60 W/120 °C). However, it proved counterproductive, resulting in a yield of only 44% after 30 minutes of reaction (Table [2], entry 6). Finally, a blank experiment conducted under the optimal conditions shown in entry 5, but in the presence of the catalyst support alone (MK-10), gave a very low conversion into the desired 3,5-disubstituted isoxazole (Table [2], entry 7). This product was accompanied by the formation of the corresponding ynone oxime (17%) and a byproduct (13%) resulting from a Michael-type addition to the starting ynone.
With these results in hand, and considering that certain copper-based catalysts have demonstrated the ability to promote the synthesis of alkynones through acyl Sonogashira coupling,[24] we envisioned a plausible one-pot dual catalytic process for the synthesis of isoxazoles promoted by our CuNPs/MK-10 catalyst. The process would start with a copper-catalyzed Sonogashira coupling between an acyl chloride and an alkyne resulting in the formation of an ynone which, after transformation into the corresponding oxime, would undergo cycloisomerization catalyzed by the same copper catalyst. This type of one-pot multicatalytic protocols are very attractive as they significantly reduce the time, waste and cost of synthetic processes, making organic synthesis more sustainable.[25] Therefore, we first proceeded with the optimization of the reaction conditions for a solvent-free acyl Sonogashira coupling, catalyzed by CuNPs/MK-10, using benzoyl chloride and phenylacetylene as model starting compounds, and triethylamine as base (Scheme [2], step a). The optimal conditions, which rendered quantitative conversion into the ynone 6a required the use of 1.5 equivalents of the acyl chloride, 3.0 equivalents of base (TEA) and 0.5 mol% Cu (10 mg of catalyst) referred to the starting phenylacetylene (see Supporting Information). The reactions were performed in a sealed tube at 80 °C for 4 hours, under nitrogen atmosphere.
Once ynone 6a was obtained, the previously optimized conditions (Table [2], entry 5) were applied for its subsequent cycloisomerization, albeit with some modifications; that is, to promote the one-pot process, TEA was used as the base in both reaction steps, re-optimizing both the amount of base and catalyst used (see Supporting Information). The optimal conditions required the use of 1.5 equivalents of TEA (210 μL) and an additional amount of the CuNPs/MK-10 catalyst (20 mg), thereby achieving the formation of isoxazole 5a with a 95% yield after 24 hours of reaction time.
During the optimization of the conditions for this one-pot two-step process, we observed the formation of a byproduct as the amount of TEA was increased (7a in Scheme [3]). Based on previous results reported by other authors,[26] we assume that this byproduct could be formed as a result of the 1,4-addition of hydroxylamine to the ynone, followed by the attack of the N-hydroxy group on the carbonyl carbon atom of the resulting unsaturated ketone, as shown in Scheme [3].
Fortunately, we were able to find reaction conditions under which the formation of this byproduct was virtually negligible. So, for the selective formation of the isoxazole product through this one-pot two-step process, the optimization of the amount of base and catalyst loading proved to be crucial. We assume that an excess of triethylamine could potentially deactivate the catalyst or favor the noncatalytic pathway leading to 7a, considering that TEA has been utilized as an additive for the synthesis of similar products.[26]
At this stage, taking into account the easy availability of carboxylic acids and the practicality of including the in situ preparation of the starting acyl chloride in the overall process, we went a step further and decided to explore the sequential one-pot process in three steps starting from the corresponding carboxylic acid. Isoxazoles 5o, 5x and 5y synthesized through this methodology are shown in Scheme [4]. It is interesting to note that, for isoxazoles 5x and 5y, there could be a competition between the classical Sonogashira coupling and the acyl Sonogashira reaction in step b of the one-pot process. However, it is noteworthy that our CuNPs/MK-10 catalyst exhibited remarkable selectivity towards the acyl Sonogashira coupling product, leaving the halogen intact and thereby offering the possibility of further functionalization.
In summary, we have presented herein a range of copper-catalyzed one-pot methodologies for the synthesis of 3,5-disubstituted isoxazoles, with high atom economy and broad synthetic utility, all of them based on the use of a versatile and readily prepared nanocatalyst consisting of copper nanoparticles supported on montmorillonite K-10 (CuNPs/MK-10). It has proven to be an efficient heterogeneous catalyst for the synthesis of isoxazoles, either through 1,3-dipolar cycloaddition reactions starting from aldehydes and alkynes, or via cycloisomerization of pre-synthesized ynones or ynones formed in situ through a CuNPs/MK-10-catalyzed acyl Sonogashira coupling between acyl chlorides and terminal alkynes. Moreover, a three-step one-pot methodology was also presented, starting from carboxylic acids and involving the in situ formation of acyl chlorides. Interestingly, when starting from halobenzoic acids, the CuNPs/MK-10 catalyst demonstrated remarkable chemoselectivity, resulting in the formation of isoxazole products while preserving the halogen intact for subsequent functionalization. In addition to being a valuable contribution to the scarce examples found in the scientific literature regarding the use of heterogeneous catalytic systems for the synthesis of isoxazoles, we believe that the simplicity and high atom economy of these copper-catalyzed methodologies will be of interest for a wide audience of synthetic organic chemists.
All starting materials were of the best available grade (Aldrich, Merck) and were used without further purification. All moisture-sensitive reactions were carried out under a nitrogen atmosphere. Anhydrous THF was freshly distilled from sodium/benzophenone ketyl. Commercially available copper(II) chloride dihydrate (97%, Sigma-Aldrich) was dehydrated by heating in an oven (150 °C, 45 min) prior to its use in the preparation of CuNPs. Analytical TLC was carried out on TLC aluminum sheets with silica gel 60 F254 (Merck), visualized under UV light and/or phosphomolybdic acid solution spray reagent (10% in ethanol), vanillin or iron(III) chloride solutions. Column chromatography was performed with Merck silica gel 60 (0.040–0.063 mm, 240–400 mesh) and hexane/EtOAc as eluent. NMR spectra were recorded on a Bruker ARX-300 spectrometer (300 MHz for 1H NMR, 75 MHz for 13C NMR and 282 MHz for 19F NMR). Chemical shifts (δ) are reported in parts per million from tetramethylsilane using the residual solvent resonance (CDCl3: 7.26 ppm for 1H NMR, 77.16 ppm for 13C NMR). Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, dd = doublet of doublets, td = triplet of doublets, tt = triplet of triplets, m = multiplet, brs = broad signal. Coupling constants (J) are reported in Hz. Melting points are uncorrected. Mass spectra (EI) were obtained at 70 eV on a Hewlett Packard HP-5890 GC/MS instrument equipped with a HP-5972 mass selective detector, or on an Agilent Model 1100 Series HPLC simultaneously coupled to a UV–visible variable wavelength detector and an ion trap analyzer mass spectrometer (Agilent Model 1100 Series LC/MSD Trap SL). Microwave-assisted reactions were carried out using a CEM Discover BenchMate microwave operating at 60 W. IR spectra were collected on a Nicolet iS50 FTIR spectrophotometer in attenuated total reflectance mode (ATR-FTIR) with a Smart iTR (Thermo Fisher Scientific) single reflection diamond (42° angle, sampling area, 1.5 mm). Elemental analyses were carried out on an Exeter Analytical Inc. CE-440 CHN analyzer.
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Preparation of CuNPs Catalysts
Anhydrous copper(II) chloride (135 mg, 1 mmol) was added to a suspension of lithium (21 mg, 3 mmol) and 4,4′-di-tert-butylbiphenyl (27 mg, 0.1 mmol) in anhyd THF (2 mL) at room temperature under a nitrogen atmosphere. The reaction mixture, which was initially dark green, rapidly turned black, indicating that the suspension of copper nanoparticles was formed. This suspension was diluted with THF (8 mL) followed by the addition of the corresponding support (800 mg). The resulting mixture was stirred at room temperature for 4 h, filtered, and the solid was washed successively with water (20 mL), ethanol (20 mL) and diethyl ether (20 mL). Finally, the catalyst was dried under vacuum.
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3,5-Disubstituted Isoxazoles (Method A); General Procedure
To the corresponding aldehyde 1 (0.5 mmol) in water (2 mL), hydroxylamine hydrochloride (38 mg, 0.55 mmol) and aq NaOH (1 M; 0.5 mL, 0.5 mmol) were added. The reaction mixture was stirred at room temperature until total conversion of the starting aldehyde into the corresponding oxime (30–60 min, monitored by TLC). The reaction was cooled on an ice bath and chloramine-T trihydrate (148 mg, 0.525 mmol) was added in small portions over 10 min, followed by the CuNPs catalyst (20 mg, 1 mol% Cu) and the alkyne (0.5 mmol). Then, the reaction mixture was heated under microwave irradiation (standard method, 60 W, 100 °C) for 30 min. After completion, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The collected organic phases were dried with Na2SO4, solvent was removed under vacuum and the product was purified by flash column chromatography (hexane/EtOAc) to give the corresponding isoxazole.
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3,5-Disubstituted Isoxazoles (Method B); General Procedure
To the corresponding aldehyde 1 (0.75 mmol) in DMF (2 mL), hydroxylamine hydrochloride (57 mg, 0.825 mmol) and NaHCO3 (63 mg, 0.75 mmol) were added. The reaction mixture was stirred at room temperature until total conversion of the starting aldehyde into the corresponding oxime (30–60 min, monitored by TLC). Next, NCS (120 mg, 0.9 mmol) was added in small portions. The reaction mixture was stirred at room temperature for 2–3 h, or heated under microwave irradiation (60 W, 40 °C, 10 min), until total conversion of the oxime into the corresponding N-hydroxyimidoyl chloride (monitored by TLC). Then, the CuNPs catalyst (20 mg, 1 mol% Cu), NaHCO3 (63 mg, 0.75 mmol) and the alkyne (0.5 mmol) were added, and the reaction mixture was heated under microwave irradiation (standard method, 60 W, 80 °C) for 30 min. After completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The collected organic phases were washed with water (10 mL) and brine (10 mL), and dried with Na2SO4. The solvent was removed under vacuum and the product was purified by flash column chromatography (hexane/EtOAc) to give the corresponding isoxazole.
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3,5-Disubstituted Isoxazoles by Cycloisomerization of Ynones (Method C); General Procedure
Over a suspension of the corresponding ynone 6 (0.25 mmol) and CuNPs/MK-10 catalyst (20 mg, 2 mol% Cu) in H2O/DMF (1:1, 2 mL), hydroxylamine hydrochloride (35 mg, 0.5 mmol) and NaHCO3 (42 mg, 0.5 mmol) were added, and the reaction mixture was heated at 120 °C in a sealed tube overnight. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The collected organic phases were washed with water (10 mL) and brine (10 mL), and dried with Na2SO4. The solvent was then removed under vacuum to give the corresponding isoxazole.
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3,5-Disubstituted Isoxazoles from Carboxylic Acids (Method D); General Procedure
The corresponding carboxylic acid (0.75 mmol) was treated with thionyl chloride (0.3 mL, 1.5 mmol). After stirring at room temperature for 1 h, the mixture was heated at 80 °C for 1 h in a sealed tube. The excess thionyl chloride was then removed under reduced pressure. Subsequently, phenylacetylene (56 μL, 0.5 mmol), triethylamine (210 μL, 1.5 mmol) and CuNPs/MK-10 catalyst (10 mg, 0.5 mol% Cu) were added. The reaction mixture was heated at 80 °C for 4 h in a sealed tube purged with nitrogen. Afterwards, a solvent mixture of DMF/H2O (1:1, 2 mL), hydroxylamine hydrochloride (70 mg, 1 mmol) and an additional amount of catalyst (20 mg, 1 mol% Cu) were added, and the reaction mixture was heated at 120 °C in a sealed tube overnight. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 10 mL). The collected organic phases were washed with water (10 mL) and brine (10 mL), and dried with Na2SO4. The solvent was then removed under vacuum and the crude product was purified by flash column chromatography (hexane/EtOAc) to obtain the corresponding isoxazole.
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3,5-Diphenylisoxazole (5a)[7b] [27]
Method A (92 mg, 83%) and method B (91 mg, 82%).
White solid; mp 141–143 °C; Rf = 0.62 (EtOAc/hexane, 1:4).
IR (ATR): 3115, 1614, 1463, 1093, 952, 763, 692 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.94–7.80 (m, 4 H), 7.56–7.40 (m, 6 H), 6.84 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 170.5, 163.1, 130.4, 130.1, 129.2, 129.1, 129.1, 127.6, 126.9, 126.0, 97.6.
MS (GC): m/z (%) = 221 (58) [M+], 220 (18), 144 (17), 105 (100), 89 (10), 77 (54), 51 (16).
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3-Phenyl-5-(p-tolyl)isoxazole (5b)[7b] [27]
Method A (84%) and method B (96 mg, 82%).
White solid; mp 136–137 °C; Rf = 0.66 (EtOAc/hexane, 1:4).
IR (ATR): 3119, 3024, 2917, 2833, 1619, 1595, 1462, 1446, 1397, 766, 688 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.94–7.77 (m, 2 H), 7.73 (d, J = 7.9 Hz, 2 H), 7.54–7.41 (m, 3 H), 7.29 (d, J = 7.9 Hz, 2 H), 6.78 (s, 1 H), 2.42 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.7, 163.1, 140.7, 130.1, 129.8, 129.4, 129.0, 126.9, 125.9, 124.9, 97.0, 21.6.
MS (GC): m/z (%) = 235 (50) [M+], 119 (100), 91 (33), 77 (10), 65 (11).
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5-(3-Chlorophenyl)-3-phenylisoxazole (5c)[7b] [28]
Method A (77 mg, 60%) and method B (64 mg, 50%).
White solid; mp 134–136 °C; Rf = 0.7 (EtOAc/hexane, 1:4).
IR (ATR): 3019, 1643, 1564, 1412, 1216, 1080, 799, 669 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.91–7.77 (m, 3 H), 7.73 (deform. ddd, J = 4.4, 1.6, 1.5 Hz, 1 H), 7.53–7.38 (m, 5 H), 6.85 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 168.9, 163.1, 135.1, 130.4, 130.2, 130.2, 129.0, 128.8, 126.8, 125.9, 123.9, 98.3.
MS (GC): m/z (%) = 257 (23) [37Cl M+], 256 (19), 255 (68) [35Cl M+], 254 (23), 144 (57), 141 (34), 139 (100), 116 (10), 113 (15), 111 (45), 89 (15), 77 (20), 75 (18), 51 (15).
#
5-(3-Methoxyphenyl)-3-phenylisoxazole (5d)[12a]
Method A (57 mg, 46%) and method B (100 mg, 80%).
Light yellow solid; mp 72–74 °C; Rf = 0.57 (EtOAc/hexane, 1:4).
IR (ATR): 3125, 3057, 2936, 2836, 2290, 2109, 1572, 1492, 1466, 1450, 1399, 1320, 1273, 1235, 1203, 1170, 1036 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.95–7.79 (m, 2 H), 7.50–7.46 (m, 3 H), 7.43–7.35 (m, 3 H), 7.00 (deform. ddd, J = 7.0, 2.3, 2.2 Hz, 1 H), 6.83 (s, 1 H), 3.89 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.4, 163.1, 160.1, 130.3, 130.2, 129.1, 128.7, 126.9, 118.4, 116.3, 111.0, 97.9, 55.6.
MS (GC): m/z (%) = 252 (11), 251 (11) [M+], 135 (100), 107 (31), 92 (20), 77 (46), 63 (12), 51 (19).
#
5-Hexyl-3-phenylisoxazole (5e)[27]
Method A (42 mg, 37%) and method B (70 mg, 61%).
Colorless oil; Rf = 0.86 (EtOAc/hexane, 1:4).
IR (neat): 3128, 3053, 2956, 2931, 2859, 1602, 1580, 1471, 1443, 1408, 768, 693 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.79–7.61 (m, 2 H), 7.39–7.26 (m, 3 H), 6.19 (s, 1 H), 2.68 (t, J = 7.6 Hz, 2 H), 1.64 (deform. tt, J = 7.6, 7.4 Hz, 2 H), 1.30–1.15 (m, 6 H), 0.82 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 174.4, 162.4, 129.9, 129.6, 129.0, 126.9, 98.9, 31.6, 28.9, 27.6, 26.9, 22.6, 14.2.
MS (GC): m/z (%) = 229 (43) [M+], 186 (18), 172 (39), 159 (36), 158 (11), 145 (11), 144 (66), 118 (13), 117 (100), 116 (16), 89 (12), 77 (42), 51 (12).
#
5-(Cyclohex-1-en-1-yl)-3-phenylisoxazole (5f)
Method A (28 mg, 25%) and method B (64 mg, 57%).
Light yellow solid; mp 75–77 °C; Rf = 0.72 (EtOAc/hexane, 1:4).
IR (ATR): 3133, 3104, 2928, 2863, 2820, 1647, 1561, 1467, 921, 766, 687 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.87–7.74 (m, 2 H), 7.49–7.39 (m, 3 H), 6.66 (tt, J = 3.9, 1.7 Hz, 1 H), 6.38 (s, 1 H), 2.47–2.33 (m, 2 H), 2.33–2.19 (m, 2 H), 1.86–1.74 (m, 2 H), 1.74–1.62 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 171.7, 162.5, 130.3, 129.9, 129.6, 129.0, 126.9, 125.5, 96.3, 25.6, 25.3, 22.2, 21.8.
MS (GC): m/z (%) = 225 (100) [M+], 224 (36), 169 (10), 168 (10), 144 (59), 117 (11), 116 (17), 109 (23), 77 (55), 66 (9), 65 (9), 51 (26).
Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 79.63; H, 6.61; N, 6.28.
#
5-((4-Methoxyphenoxy)methyl)-3-phenylisoxazole (5g)
Method A (59 mg, 50%) and method B (107 mg, 90%).
White solid; mp 84–85 °C; Rf = 0.67 (EtOAc/hexane, 1:4).
1H NMR (300 MHz, CDCl3): δ = 7.85–7.77 (m, 2 H), 7.49–7.42 (m, 3 H), 6.98–6.89 (m, 2 H), 6.89–6.81 (m, 2 H), 6.63 (s, 1 H), 5.16 (s, 2 H), 3.78 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 168.8, 162.5, 154.7, 151.9, 130.1, 128.9, 128.8, 126.9, 116.1, 114.8, 101.3, 62.4, 55.7.
MS (GC): m/z (%) = 281 (25) [M+], 123 (100), 95 (16), 77 (19), 63 (5), 51 (8).
Anal. Calcd for C17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.75; H, 5.29; N, 5.41.
#
5-(Phenoxymethyl)-3-phenylisoxazole (5h)
Method A (40 mg, 32%) and method B (67 mg, 67%).
Cream solid; mp 65–66 °C; Rf = 0.54 (EtOAc/hexane, 1:4).
IR (ATR): 3117, 3031, 2931, 2865, 1600, 1580, 1491, 1246, 773, 746, 687 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.88–7.74 (m, 2 H), 7.52–7.40 (m, 3 H), 7.34 (t, J = 7.8 Hz, 2 H), 7.08–6.96 (m, 3 H), 6.66 (s, 1 H), 5.21 (s, 2 H).
13C NMR (75 MHz, CDCl3): δ = 168.7, 162.6, 157.9, 130.2, 129.8, 129.0, 128.9, 127.0, 122.0, 114.9, 101.5, 61.5.
MS (GC): m/z (%) = 251 (49) [M+], 159 (12), 158 (100), 144 (12), 105 (12), 103 (11), 77 (49), 51 (14).
Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21; N, 5.57. Found: C, 76.16; H, 5.17; N, 5.60.
#
(3-Phenylisoxazol-5-yl)methanol (5i)[12a]
Method B (52 mg, 60%).
Light yellow solid; mp 51–53 °C; Rf = 0.13 (EtOAc/hexane, 1:4).
IR (KBr): 3368, 2924, 1607, 1445, 1406, 1168, 1037, 768, 693 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.85–7.72 (m, 2 H), 7.50–7.41 (m, 3 H), 6.57 (s, 1 H), 4.82 (s, 2 H), 2.58 (brs s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 172.0, 162.6, 130.2, 129.1, 128.9, 126.9, 100.2, 56.7.
MS (GC): m/z (%) = 175 (38) [M+], 145 (11), 144 (100), 116 (30), 89 (12), 77 (44), 51 (14).
#
3-Phenyl-5-(pyridin-2-yl)isoxazole (5j)[29]
Method B (58 mg, 52%).
White solid; mp 84–85 °C; Rf = 0.54 (EtOAc/hexane, 2:3).
IR (ATR): 3058, 2358, 1701, 1576, 1450, 1139, 763, 689 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.72 (d, J = 4.8 Hz, 1 H), 7.97 (d, J = 7.9 Hz, 1 H), 7.93–7.81 (m, 3 H), 7.56–7.43 (m, 3 H), 7.36 (dd, J = 7.5, 4.8 Hz, 1 H), 7.26 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 169.9, 163.4, 150.2, 146.7, 137.3, 130.3, 129.1, 129.0, 127.0, 124.6, 121.0, 100.4.
MS (GC): m/z (%) = 223 (11), 222 (65) [M+], 221 (26), 194 (13), 193 (12), 178 (40), 145 (11), 144 (100), 116 (22), 89 (12), 78 (26), 77 (38), 63 (10), 51 (26).
#
5-(Hept-6-yn-1-yl)-3-phenylisoxazole (5k)
Method B (54 mg, 45%).
Light yellow oil; Rf = 0.71 (EtOAc/hexane, 1:4).
IR (neat): 3293, 2935, 2858, 1599, 1570, 1469, 1444, 1400, 768, 690 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.85–7.73 (m, 2 H), 7.49–7.39 (m, 3 H), 6.30 (s, 1 H), 2.81 (t, J = 7.6 Hz, 2 H), 2.21 (td, J = 6.7, 2.5 Hz, 2 H), 1.95 (t, J = 2.6 Hz, 1 H), 1.77 (tt, J = 7.5, 7.5 Hz, 2 H), 1.66–1.44 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 174.0, 162.4, 129.9, 129.5, 129.0, 126.8, 99.0, 84.4, 68.6, 28.2, 28.1, 27.2, 26.8, 18.4.
MS (GC): m/z (%) = 239 (10) [M+], 238 (27), 210 (23), 183 (10), 182 (20), 172 (13), 159 (27), 156 (10), 145 (13), 144 (100), 136 (40), 130 (12), 118 (16), 117 (83), 116 (29), 108 (10), 107 (14), 104 (14), 103 (10), 94 (13), 93 (11), 89 (20), 79 (18), 78 (12), 77 (84), 63 (10), 55 (22), 53 (12), 51 (27).
Anal. Calcd for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C, 79.95; H, 7.11; N, 5.89.
#
3-(4-Methoxyphenyl)-5-phenylisoxazole (5l)[7b] [13]
Method B (114 mg, 91%) and method C (56 mg, 90%).
Light yellow solid; mp 120–122 °C; Rf = 0.39 (EtOAc/hexane, 1:4).
IR (ATR): 3115, 2921, 2851, 1613, 1570, 1529, 1494, 1447, 1430, 1299, 1253, 1178, 1116, 1073, 1032 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.89–7.75 (m, 4 H), 7.55–7.41 (m, 3 H), 7.04–6.96 (m, 2 H), 6.78 (s, 1 H), 3.87 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.3, 162.7, 161.1, 130.3, 129.1, 128.3, 127.7, 126.0, 121.8, 114.5, 97.4, 55.5.
MS (GC): m/z (%) = 251 (51) [M+], 174 (13), 149 (13), 105 (100), 77 (53).
#
3-(4-Chlorophenyl)-5-phenylisoxazole (5m)[7b] [13]
Method B (106 mg, 83%).
White solid; mp 172–174 °C; Rf = 0.57 (EtOAc/hexane, 1:4).
IR (ATR): 3112, 2923, 1591, 1446, 1048, 1070, 759, 670 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.87–7.76 (m, 4 H), 7.55–7.43 (m, 5 H), 6.81 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 170.9, 162.1, 136.2, 130.5, 129.4, 129.2, 128.2, 127.8, 127.4, 126.0, 97.4.
MS (GC): m/z (%) = 257 (9) [37Cl M+], 255 (27) [35Cl M+], 105 (100), 77 (40), 51 (9).
#
3-(Naphthalen-1-yl)-5-phenylisoxazole (5n)[7b] [30]
Method B (125 mg, 92%).
Orange oil; Rf = 0.61 (EtOAc/hexane, 1:4).
IR (neat): 3050, 2960, 1595, 1413, 1252, 1175, 1055, 970, 936, 760 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.49–8.38 (m, 1 H), 8.03–7.86 (m, 4 H), 7.77 (dd, J = 7.1, 1.3 Hz, 1 H), 7.64–7.44 (m, 6 H), 6.86 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 169.9, 163.3, 133.9, 131.2, 130.4, 130.4, 129.2, 128.6, 127.9, 127.6, 127.2, 127.1, 126.4, 126.0, 125.8, 125.3, 101.1.
MS (GC): m/z (%) = 272 (12), 271 (61) [M+], 270 (44), 194 (18), 169 (10), 139 (10), 127 (12), 121 (14), 105 (100), 77 (62), 51 (11).
#
5-Phenyl-3-(o-tolyl)isoxazole (5o)[31]
Method B (106 mg, 90%) and method D (118 mg, 95%).
White solid; mp 60–62 °C; Rf = 0.72 (EtOAc/hexane, 1:4).
IR (ATR): 3133, 2925, 2830, 1631, 1450, 1353, 1095, 1017, 789, 685 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.90–7.79 (m, 2 H), 7.60–7.53 (m, 1 H), 7.53–7.40 (m, 3 H), 7.40–7.22 (m, 3 H), 6.69 (s, 1 H), 2.53 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 169.6, 163.8, 137.0, 131.2, 130.3, 129.6, 129.6, 129.1, 129.0, 127.6, 126.1, 126.0, 100.3, 21.3.
MS (GC): m/z (%) = 236 (13), 235 (80) [M+], 234 (100), 158 (62), 130 (47), 105 (75), 103 (13), 102 (10), 91 (10), 89 (15), 77 (81), 65 (14), 51 (19).
#
3-(2-Fluorophenyl)-5-phenylisoxazole (5p)[30]
Method B (112 mg, 94%).
Cream solid; mp 83–84 °C; Rf = 0.68 (EtOAc/hexane, 1:4).
IR (ATR): 3119, 2345, 1594, 1225, 1091, 946, 739, 522 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.05 (td, J = 7.6, 1.8 Hz, 1 H), 7.91–7.81 (m, 2 H), 7.57–7.39 (m, 4 H), 7.31–7.19 (m, 2 H), 6.99 (d, J = 3.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 170.43 (d, J = 1.8 Hz), 160.46 (d, J = 251.5 Hz), 158.48 (d, J = 1.4 Hz), 131.78 (d, J = 8.6 Hz), 130.4, 129.24 (d, J = 3.0 Hz), 129.2, 127.5, 126.0, 124.77 (d, J = 3.5 Hz), 117.31 (d, J = 11.8 Hz), 116.53 (d, J = 21.9 Hz), 100.17 (d, J = 9.2 Hz).
19F NMR (282 MHz, CDCl3): δ = –114.27.
MS (GC): m/z (%) = 239 (45) [M+], 162 (10), 106 (8), 105 (100), 77 (45), 51 (10).
#
3-(4-Nitrophenyl)-5-phenylisoxazole (5q)[32]
Method B (93 mg, 70%).
Light yellow solid; mp 221–223 °C; Rf = 0.77 (EtOAc/hexane, 1:1).
IR (ATR): 3085, 1568, 1520, 1347, 861 cm–1.
1H NMR (300 MHz, DMSO-d 6): δ = 8.39 (d, J = 8.4 Hz, 2 H), 8.18 (d, J = 8.4 Hz, 2 H), 8.00–7.84 (m, 2 H), 7.77 (s, 1 H), 7.66–7.48 (m, 3 H).
13C NMR (75 MHz, DMSO-d 6): δ = 170.5, 161.2, 148.4, 134.6, 130.8, 129.4, 127.8, 126.5, 125.6, 124.4, 99.1.
MS (GC): m/z (%) = 266 (35) [M+], 106 (8), 105 (100), 96 (7), 77 (50), 51 (10).
#
5-Phenyl-3-(thiophen-2-yl)isoxazole (5t)[33]
Method B (57 mg, 50%).
White solid; mp 110–111 °C; Rf = 0.61 (EtOAc/hexane, 1:4).
IR (ATR): 3117, 1615, 1576, 1489, 1446, 1425, 1344, 1071, 949, 916, 851, 755, 667 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.88–7.76 (m, 2 H), 7.59–7.37 (m, 5 H), 7.14 (dd, J = 5.1, 3.6 Hz, 1 H), 6.76 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 170.5, 158.3, 131.0, 130.5, 129.1, 127.8, 127.7, 127.5, 127.3, 126.0, 97.6.
MS (GC): m/z (%) = 227 (80) [M+], 199 (6), 125 (16), 105 (100), 77 (89), 51 (31).
#
2-Methoxy-4-(5-phenylisoxazol-3-yl)phenol (5u)
Method B (102 mg, 76%).
White solid; mp 125–127 °C; Rf = 0.65 (EtOAc/hexane, 1:1).
IR (ATR): 3301, 2993, 2830, 2224, 1610, 1569, 1530, 1037, 932, 860, 793 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.90–7.78 (m, 2 H), 7.53–7.44 (m, 4 H), 7.31 (dd, J = 8.2, 1.9 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 6.79 (s, 1 H), 5.89 (s, 1 H), 3.98 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.3, 162.9, 147.6, 147.0, 130.3, 129.1, 127.6, 126.0, 121.4, 120.8, 114.7, 108.9, 97.4, 56.2.
MS (GC): m/z (%) = 268 (10), 267 (55) [M+], 224 (10), 190 (9), 165 (16), 106 (9), 105 (100), 77 (43), 51 (9).
Anal. Calcd for C16H13NO3: C, 71.90; H, 4.90; N, 5.24. Found: C, 71.62; H, 4.87; N, 5.26.
#
2-Methoxy-4-(5-(pyridin-2-yl)isoxazol-3-yl)phenol (5v)
Method B (117 mg, 87%).
Light yellow solid; mp 128–129 °C; Rf = 0.41 (EtOAc/hexane, 1:1).
IR (ATR): 3341, 3150, 2981, 1580, 1534, 1492, 1481, 1260, 1026, 785 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.69 (d, J = 4.8 Hz, 1 H), 7.94 (d, J = 7.9 Hz, 1 H), 7.83 (t, J = 7.9 Hz, 1 H), 7.45 (s, 1 H), 7.39–7.29 (m, 2 H), 7.20 (s, 1 H), 6.99 (d, J = 8.2 Hz, 1 H), 6.32 (brs s, 1 H), 3.92 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 169.5, 163.1, 150.1, 147.7, 147.1, 146.6, 137.3, 124.6, 121.0, 121.0, 120.8, 114.9, 109.0, 100.3, 56.1.
MS (GC): m/z (%) = 269 (17), 268 (100) [M+], 191 (11), 190 (94), 162 (57), 119 (11), 79 (12), 78 (39), 52 (13), 51 (18).
Anal. Calcd for C15H12N2O3: C, 67.16; H, 4.51; N, 10.44. Found: C, 66.90; H, 4.48; N, 10.39.
#
4-(5-(4-Bromophenyl)isoxazol-3-yl)-2-methoxyphenol (5w)
Method B (121 mg, 70%).
Light yellow solid; mp 167–169 °C; Rf = 0.57 (EtOAc/hexane, 2:3).
IR (ATR): 3265, 3090, 2997, 2832, 1609, 1464, 1281, 1028, 786 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.68 (d, J = 8.4 Hz, 2 H), 7.61 (d, J = 8.4 Hz, 2 H), 7.46 (d, J = 1.8 Hz, 1 H), 7.28 (dd, J = 8.2, 1.8 Hz, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 6.77 (s, 1 H), 5.92 (brs s, 1 H), 3.97 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 169.2, 163.0, 147.7, 147.0, 132.4, 127.4, 126.5, 124.6, 121.1, 120.8, 114.7, 108.8, 97.8, 56.2.
MS (GC): m/z (%) = 347 (47) [81Br M+], 346 (10), 345 (48) [79Br M+], 190 (14), 185 (97), 183 (100), 165 (41), 162 (10), 157 (29), 155 (30), 76 (18), 75 (17), 63 (11), 52 (12), 51 (12), 50 (11).
Anal. Calcd for C16H12BrNO3: C, 55.51; H, 3.49; N, 4.05. Found: C, 55.27; H, 3.46; N, 4.07.
#
3-(2-Bromophenyl)-5-phenylisoxazole (5x)[28]
Method D (120 mg, 80%).
Yellow solid; mp 74–76 °C; Rf = 0.55 (EtOAc/hexane, 1:4).
IR (ATR): 3150, 3025, 1635, 1448, 1216, 948, 695 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.95–7.84 (m, 3 H), 7.71 (dd, J = 8.1, 1.2 Hz, 1 H), 7.52–7.38 (m, 4 H), 7.32–7.21 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 168.1, 162.8, 134.3, 131.2, 130.2, 130.2, 129.1, 129.0, 128.4, 127.8, 127.0, 121.2, 102.4.
MS (GC): m/z (%) = 301 (43) [81Br M+], 299 (43) [79Br M+], 185 (100), 183 (99.7), 165 (14), 157 (27), 155 (27), 144 (43), 89 (34), 51 (27).
#
3-(2-Iodophenyl)-5-phenylisoxazole (5y)
Method D (121 mg, 70%).
Yellow solid; mp 48–49 °C; Rf = 0.56 (EtOAc/hexane, 1:4).
IR (ATR): 3154, 3093, 2921, 1593, 1450, 1001, 947, 759, 682 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.03 (dd, J = 7.8, 1.2 Hz, 1 H), 7.93–7.86 (m, 2 H), 7.75 (dd, J = 7.7, 1.8 Hz, 1 H), 7.55–7.42 (m, 4 H), 7.19 (s, 1 H), 7.15 (td, J = 7.8, 1.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 170.7, 162.6, 141.0, 132.7, 131.4, 130.4, 130.2, 129.1, 129.1, 128.5, 127.0, 102.0, 95.5.
MS (GC): m/z (%) = 347 (100) [M+], 231 (10), 220 (50), 203 (44), 165 (33), 144 (29), 89 (61), 76 (36).
Anal. Calcd for C15H10INO: C, 51.90; H, 2.90; N, 4.03. Found: C, 51.68; H, 2.88; N, 4.01.
#
#
Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2193-4701.
- Supporting Information
-
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- 9b Santana-Romo F, Lagos CF, Duarte Y, Castillo F, Moglie Y, Maestro MA, Charbe N, Zacconi FC. Molecules 2020; 25: 491
- 10a Kolb HC, Finn MG, Sharpless KB. Angew. Chem. Int. Ed. 2001; 40: 2004
- 10b Tornøe C. W., Meldal M.; Peptidotriazoles: Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions on Solid-Phase, In Peptides: The Wave of the Future, Proceedings of the Second International and the Seventeenth American Peptide Symposium:San Diego, California, U.S.A., June 9–14, 2001; Lebl, M.; Houghten, R. A., Eds.; American Peptide Society/Kluwer Academic Publishers: San Diego, 2001, 263.
- 10c Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. 2002; 41: 2596
- 10d Agard NJ, Prescher JA, Bertozzi CR. J. Am. Chem. Soc. 2004; 126: 15046
- 10e Castelvecchi D, Ledford H. Nature 2022; 610: 242
- 11a Hansen TV, Wu P, Fokin VV. J. Org. Chem. 2005; 70: 7761
- 11b Grecian S, Fokin VV. Angew. Chem. Int. Ed. 2008; 47: 8285
- 12a Meena DR, Maiti B, Chanda K. Tetrahedron Lett. 2016; 57: 5514
- 12b DeKorver KA, Li H, Lohse AG, Hayashi R, Lu Z, Zhang Y, Hsung RP. Chem. Rev. 2010; 110: 5064
- 12c Evano G, Coste A, Jouvin K. Angew. Chem. Int. Ed. 2010; 49: 2840
- 12d Oakdale JS, Sit RK, Fokin VV. Chem. Eur. J. 2014; 20: 11101
- 13a Bharate SB, Padala AK, Dar BA, Yadav RR, Singh B, Vishwakarma RA. Tetrahedron Lett. 2013; 54: 3558
- 13b Chanda K, Rej S, Huang MH. Nanoscale 2013; 5: 12494
- 13c Pardeshi SS, Labhane PK, Disale ST, More DH, Sapkal BM. ChemistrySelect 2022; 7: e202201818
- 14 MacDonald JE, Kelly JA, Veinot JG. C. Langmuir 2007; 23: 9543
- 15a Denmark SE, Kallemeyn JM. J. Org. Chem. 2005; 70: 2839
- 15b Letourneau JJ, Riveillo C, Ohlmeyer MH. J. Tetrahedron Lett. 2007; 48: 1739
- 16 Zhang X.-W, He X.-L, Yan N, Zheng H.-X, Hu X.-G. J. Org. Chem. 2020; 85: 15726
- 17a McIntosh ML, Naffziger MR, Ashburn BO, Zakharov LN, Carter RG. Org. Biomol. Chem. 2012; 10: 9204
- 17b Wang G.-W, Cheng M.-X, Ma R.-S, Yang S.-D. Chem. Commun. 2015; 51: 6308
- 17c Himo F, Lovell T, Hilgraf R, Rostovtsev VV, Noodleman L, Sharpless KB, Fokin VV. J. Am. Chem. Soc. 2005; 127: 210
- 17d Willy B, Rominger F, Müller TJ. J. Synthesis 2008; 293
- 17e Wang X.-D, Zhu L.-H, Liu P, Wang X.-Y, Yuan H.-Y, Zhao Y.-L. J. Org. Chem. 2019; 84: 16214
- 18a Moglie Y, Buxaderas E, Mancini A, Alonso F, Radivoy G. ChemCatChem 2019; 11: 1487
- 18b Bjerg EE, Marchán-García J, Buxaderas E, Moglie Y, Radivoy G. J. Org. Chem. 2022; 87: 13480
- 18c Nador F, Mancebo-Aracil J, Zanotto D, Ruiz-Molina D, Radivoy G. RSC Adv. 2021; 11: 2074
- 19 Mancebo-Aracil J, Alonso B, Radivoy G. Chem. Proc. 2021; 3: 103
- 20a Beltrame P, Comotti A, Vegleo C. Chem. Commun. 1967; 996
- 20b Dondoni A, Mangini A, Ghersetti S. Tetrahedron Lett. 1966; 7: 4789
- 21a Li J, Hu M, Li C, Li C, Li J, Wu W, Jiang H. Adv. Synth. Catal. 2018; 360: 2707
- 21b Liu X, Hong D, She Z, Hersh WH, Yoo B, Chen Y. Tetrahedron 2018; 74: 6593
- 21c Hueda M, Ikeda Y, Sato A, Ito Y, Kakiuchi M, Shono H, Miyoshi T, Naito T, Miyata O. Tetrahedron 2011; 67: 4612
- 21d Li C, Li J, Zhou F, Li C, Wu W. J. Org. Chem. 2019; 84: 11958
- 22 Ueda M, Sugita S, Sato A, Miyoshi T, Miyata O. J. Org. Chem. 2012; 77: 9344
- 23 Duan M, Hou G, Zhao Y, Zhu C, Song C. J. Org. Chem. 2022; 87: 11222
- 24a Wang K, Yang L, Zhao W, Cao L, Sun Z, Zhang F. Green Chem. 2017; 19: 1949
- 24b Sun W, Wang Y, Wu X, Yao X. Green Chem. 2013; 15: 2356
- 25 Martínez S, Veth L, Lainer B, Dydio P. ACS Catal. 2021; 11: 3891
- 26 Harigae R, Moriyama K, Togo H. J. Org. Chem. 2014; 79: 2049
- 27 Yoshimura A, Middleton KR, Todora AD, Kastern BJ, Koski SR, Maskaev AV, Zhdankin VV. Org. Lett. 2013; 15: 4010
- 28 Kumar GR, Kumar YK, Reddy MS. Chem. Commun. 2016; 52: 6589
- 29 González-Soria MJ, Alonso F. Adv. Synth. Catal. 2019; 361: 5005
- 30 Carloni L.-E, Mohnani S, Bonifazi D. Eur. J. Org. Chem. 2019; 7322
- 31 Mohammed S, Vishwakarma RA, Bharate SB. RSC Adv. 2015; 5: 3470
- 32 Khairnar PV, Lung T.-H, Lin Y.-J, Wu C.-Y, Koppolu SR, Edukondalu A, Karanam P, Lin W. Org. Lett. 2019; 21: 4219
- 33 Li Z, Wen G, Fu R, Yang J. J. Chem. Res. 2016; 40: 643
For some examples about the use of isoxazoles as synthetic intermediates, see:
Some examples about synthetic methods for the construction of isoxazole rings not included in refs. 4–6:
For some recent examples, see:
Corresponding Author
Publication History
Received: 01 August 2023
Accepted after revision: 17 October 2023
Accepted Manuscript online:
17 October 2023
Article published online:
20 November 2023
© 2023. Thieme. All rights reserved
Georg Thieme Verlag KG
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-
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- 17a McIntosh ML, Naffziger MR, Ashburn BO, Zakharov LN, Carter RG. Org. Biomol. Chem. 2012; 10: 9204
- 17b Wang G.-W, Cheng M.-X, Ma R.-S, Yang S.-D. Chem. Commun. 2015; 51: 6308
- 17c Himo F, Lovell T, Hilgraf R, Rostovtsev VV, Noodleman L, Sharpless KB, Fokin VV. J. Am. Chem. Soc. 2005; 127: 210
- 17d Willy B, Rominger F, Müller TJ. J. Synthesis 2008; 293
- 17e Wang X.-D, Zhu L.-H, Liu P, Wang X.-Y, Yuan H.-Y, Zhao Y.-L. J. Org. Chem. 2019; 84: 16214
- 18a Moglie Y, Buxaderas E, Mancini A, Alonso F, Radivoy G. ChemCatChem 2019; 11: 1487
- 18b Bjerg EE, Marchán-García J, Buxaderas E, Moglie Y, Radivoy G. J. Org. Chem. 2022; 87: 13480
- 18c Nador F, Mancebo-Aracil J, Zanotto D, Ruiz-Molina D, Radivoy G. RSC Adv. 2021; 11: 2074
- 19 Mancebo-Aracil J, Alonso B, Radivoy G. Chem. Proc. 2021; 3: 103
- 20a Beltrame P, Comotti A, Vegleo C. Chem. Commun. 1967; 996
- 20b Dondoni A, Mangini A, Ghersetti S. Tetrahedron Lett. 1966; 7: 4789
- 21a Li J, Hu M, Li C, Li C, Li J, Wu W, Jiang H. Adv. Synth. Catal. 2018; 360: 2707
- 21b Liu X, Hong D, She Z, Hersh WH, Yoo B, Chen Y. Tetrahedron 2018; 74: 6593
- 21c Hueda M, Ikeda Y, Sato A, Ito Y, Kakiuchi M, Shono H, Miyoshi T, Naito T, Miyata O. Tetrahedron 2011; 67: 4612
- 21d Li C, Li J, Zhou F, Li C, Wu W. J. Org. Chem. 2019; 84: 11958
- 22 Ueda M, Sugita S, Sato A, Miyoshi T, Miyata O. J. Org. Chem. 2012; 77: 9344
- 23 Duan M, Hou G, Zhao Y, Zhu C, Song C. J. Org. Chem. 2022; 87: 11222
- 24a Wang K, Yang L, Zhao W, Cao L, Sun Z, Zhang F. Green Chem. 2017; 19: 1949
- 24b Sun W, Wang Y, Wu X, Yao X. Green Chem. 2013; 15: 2356
- 25 Martínez S, Veth L, Lainer B, Dydio P. ACS Catal. 2021; 11: 3891
- 26 Harigae R, Moriyama K, Togo H. J. Org. Chem. 2014; 79: 2049
- 27 Yoshimura A, Middleton KR, Todora AD, Kastern BJ, Koski SR, Maskaev AV, Zhdankin VV. Org. Lett. 2013; 15: 4010
- 28 Kumar GR, Kumar YK, Reddy MS. Chem. Commun. 2016; 52: 6589
- 29 González-Soria MJ, Alonso F. Adv. Synth. Catal. 2019; 361: 5005
- 30 Carloni L.-E, Mohnani S, Bonifazi D. Eur. J. Org. Chem. 2019; 7322
- 31 Mohammed S, Vishwakarma RA, Bharate SB. RSC Adv. 2015; 5: 3470
- 32 Khairnar PV, Lung T.-H, Lin Y.-J, Wu C.-Y, Koppolu SR, Edukondalu A, Karanam P, Lin W. Org. Lett. 2019; 21: 4219
- 33 Li Z, Wen G, Fu R, Yang J. J. Chem. Res. 2016; 40: 643
For some examples about the use of isoxazoles as synthetic intermediates, see:
Some examples about synthetic methods for the construction of isoxazole rings not included in refs. 4–6:
For some recent examples, see:
