Isomerizable (E/Z)-alkynyl-O-methyl oximes employing TMSCl–NCS in chlorinative cyclization for the direct synthesis of 4-chloroisoxazoles

Abstract

For the first time, 4-chloroisoxazoles are directly synthesized in moderate to excellent yields from (E/Z)-alkynyl-O-methyl oximes via chlorinative cyclization. The synthesis employs the combination of N-chlorosuccinimide (NCS) and chlorotrimethylsilane (TMSCl) in nitromethane solvent where chlorine (Cl₂) and hydrochloric acid (HCl) are generated in situ. In addition, the current protocol is applicable to the synthesis of 4-bromo- and 4-iodoisoxazoles when N-bromosuccinimide (NBS) and N-iodosuccinimide (NIS), respectively, are employed in place of NCS. The current method can improve the overall efficiency of the preparation of 4-haloisoxazoles starting from the step where alkynyl-O-methyl oximes are prepared since (E)-isomers can isomerize and cyclize under the conditions.

---

Introduction

Isoxazoles are an important structural motif¹ found in many biologically active compounds and currently marketed drugs, such as valdecoxib and oxacillin, a non-steroidal anti-inflammatory drug and a β-lactamase-resistant antibiotic drug, respectively. Pertaining to the medicinal properties of compounds, several studies have shown that the inclusion of halogen atoms can improve their biological activities as compared to the non-halogenated variants.² Due to these important pharmacological aspects of halogenated compounds and the roles the isoxazole nucleus plays in medicinal chemistry, preparative methods for halogenated isoxazoles are of interest among organic and medicinal chemists. Furthermore, the halogen atoms in halogenated isoxazoles can serve as synthetic handles for a variety of C–C and C–heteroatom bond formations via cross-coupling reactions,³ thus facilitating further functionalization and increasing the molecular diversity.

One of the most widely used strategies for the construction of the 4-haloisoxazole nucleus in general is the cyclization of (Z)-alkynyl-O-methyl oximes mediated by electrophilic halogens, which are presently available only for the preparation of 4-fluoro-, 4-bromo- and 4-iodoisoxazoles. As illustrated in Scheme 1, Ryu⁴ recently utilized the combination of a gold catalyst and an electrophilic fluorine source to synthesize 4-fluoroisoxazoles from (Z)-only alkynyl-O-methyl oximes. Previously, Larock⁵ also showed that reagents such as Br₂ and ICl could be employed to synthesize 4-bromo- and 4-iodoisoxazole derivatives, respectively, via the cyclization of also (Z)-only alkynyl-O-methyl oximes.

Scheme 1 Halogenative cyclization strategy employed in the synthesis of 4-haloisoxazoles.

For the synthesis of 4-chloroisoxazole derivatives, no procedure has been reported to date for the direct cyclization from alkynyl-O-methyl oximes. The current synthesis of 4-chloroisoxazole derivatives relies on the chlorination of 4-unsubstituted isoxazole compounds under strongly acidic (NCS and sulfuric acid in refluxing acetic acid) or oxidative (hydrogen chloride and hydrogen peroxide in refluxing acetic acid) conditions.⁶ In this work, we aim to search for the new method which could prepare 4-chloroisoxazoles by direct conversion of alkynyl-O-methyl oximes, which would provide a useful and concise synthetic access to such compounds. We recently reported a halogenation procedure for aromatic compounds which relies on the in situ generation of interhalogen species (X–Cl) and hydrochloric acid (HCl) from chlorotrimethylsilane (TMSCl) and N-halosuccinimide (NXS) in wet acetonitrile.⁷ For the combination of TMSCl and N-chlorosuccinimide (NCS), we hypothesized that chlorine (Cl₂) generated under the conditions may enable the direct formation of 4-chloroisoxazoles via electrophilic Cl₂-induced cyclization, thus constituting the first direct synthesis of 4-chloroisoxazoles via chlorinative cyclization of alkynyl-O-methyl oximes (Scheme 2). In addition, we also envisioned that the inherently acidic conditions may be advantageous in isomerizing the normally unreactive (E)-alkynyl-O-methyl oximes to the (Z)-isomers appropriate for the cyclization.

Scheme 2 Proposed mechanism of the reaction.

Results and discussion

We started the investigation of our proposed cyclization of alkynyl-O-methyl oximes with compound 1a which was obtained only as (Z)-isomer after purification and can be prepared in good overall yield from benzaldehyde and phenylacetylene.⁸ Compound 1a was subjected to different conditions as summarized in Table 1.

Table 1 Optimization for the cyclization of (Z)-alkynyl-O-methyl oximes 1a

Entry	NCS (equiv.)	TMSCl (equiv.)	[1a] (M)	Solvent	Conversion^a (%)
a Conversions were determined by ^1H NMR.
1	1.1	0.1	0.4	CH3CN	17
2	1.1	0.1	0.4	CH3NO2	53
3	1.1	1.0	0.4	CH3NO2	46
4	1.1	1.0	0.1	CH3NO2	>99
5	1.1	1.0	0.1	THF	68
6	1.1	1.0	0.1	DCM	28
7	1.1	0.5	0.1	CH3NO2	52
8	1.1	—	0.1	CH3NO2	NR
9	—	1.0	0.1	CH3NO2	NR

---

We first applied our original conditions⁷ to substrate 1a in commercial-grade CH₃CN at rt for 1 h (entry 1) which resulted in only 17% conversion. We next studied the effects of other solvents. Changing the solvent from CH₃CN to CH₃NO₂ resulted in a significantly improved conversion (53%, entry 2). Next, more TMSCl (1.0 equiv.) was employed but this resulted in a slightly lower conversion (46%, entry 3), which may have been due to the concentration effect. Therefore, the concentration of the substrate was lowered to 0.1 M (entry 4) which led to >99% conversion to product 2a. After the optimal concentration was established, we next investigated additional solvents, including THF and DCM, both of which were found to be less effective, giving lower conversions than in CH₃NO₂ (entries 5–6). We next attempted the reaction in CH₃NO₂ with lower equivalent of TMSCl (0.5 equiv.) and found the conversion dropping to 52% (entry 7). Additionally, we attempted the reaction with NCS only (entry 8) and TMSCl only (entry 9) and no reaction occurred in either case. This indicated that both reagents were required for the successful conversion of the substrate. Moreover, this outcome also supported the proposed mechanism of formation of product (Scheme 2), which required chlorine, generated from combination of NCS and TMSCl, to induce the cyclization by activating the triple bond. Therefore, the optimal conditions required the reaction to be conducted in CH₃NO₂ at room temperature using 1.1 equiv. of NCS and 1.0 equiv. of TMSCl at 0.1 M concentration of substrate for 1 h.

With the optimal conditions in hand, we began to study the scope of alkynyl-O-methyl oximes, beginning with R¹ and R² as aryl groups. The preparation of these substrates started from ynones, which could be prepared by lithium acetylide addition to aldehydes followed by oxidation of the resulting propargylic alcohols⁸ or by Sonogashira coupling between acid chlorides and terminal alkynes.⁹ The condensation of ynones with methoxyamine hydrochloride salt¹⁰ then afforded the corresponding alkynyl-O-methyl oximes in moderate to good overall yields (Scheme 3). Substrates employed in Table 2 (R¹ = R² = aryl groups) were obtained only as (Z)-isomers after purification while almost all substrates employed in Table 3 (R¹ = alkyl groups, R² = Ph or alkyl groups) were obtained as (E/Z)-isomeric mixtures. The results of the cyclization of these compounds are summarized below.

Scheme 3 Preparation of alkynyl-O-methyl oximes 1.^8–10

Table 2 Scope of intramolecular cyclization of (Z)-alkynyl-O-methyl oximes 1^a

a Isolated yields.b The reaction required heating at reflux for 1 h.

---

Table 3 Intramolecular cyclization of mixtures of (E/Z)-alkynyl-O-methyl oximes 1^a

a Isolated yields.b Reaction time was 5 h.c 1.0 equiv. of TMSCl was employed.

---

As shown in Table 2, in most cases the reactions proceeded under mild conditions (rt, 1 h). For the substrate with R¹ = R² = Ph groups, the reaction afforded quantitative yield of the desired product (2a-Cl). We then varied the electronic property of R¹ while keeping R² as the phenyl group. With R¹ being an electronically neutral o-tolyl ring, the cyclization proceeded to afford the corresponding 4-chloroisoxazole 2b in 83% yield. We next attempted the reactions with substrates containing mildly electron-withdrawing biphenyl systems. For the substrate containing the p-biphenyl group (1c), the desired product (2c) was obtained uneventfully in 69%. For the o-biphenyl substrate (1d), the desired product (2d) was obtained in 59% along with 25% of by-product 3d formed via the intramolecular cyclization by the adjacent o-phenyl ring. This result showed the tethered o-biphenyl group to be the competing nucleophile (leading to 3d), although the reaction with the methoxy oxygen as the nucleophile (leading to 2d) was still more prevalent. The structure of by-product 3d was proposed and confirmed by ¹H and ¹³C NMR spectroscopy, both 1D and 2D techniques, as well as HRMS, however, the geometry of the vinyl chloride could not be conclusively assigned. In case of R¹ = p-OMe-phenyl group, the reaction proceeded to give no desired cyclized product (2e), instead the formation of complex mixture was observed. We speculated that when R¹ = aryl group containing electron-donating substituent, it became competitive in reacting with the electrophilic chlorine and underwent other undesired reaction pathways under the conditions faster than the cyclization. Next, substrates with R¹ = p-F-, p-Cl- and m-Cl-phenyl groups were examined. The reactions proceeded uneventfully to give the desired products 2f, 2g, and 2h in 88%, 75% and 96% yields, respectively. In these cases, the halogen atom at the meta-position of the aryl ring of R¹ seemed to facilitate the cyclization to a greater degree. For the substrate containing p-Br-phenyl group (1i), the reaction was more sluggish and required reflux for 1 h for a complete conversion to afford product 2i in 70% yield. We next explored substrates containing a variety of R² while keeping R¹ = Ph (1j–1l). With R² = p-OMe-phenyl group (1j), the reaction proceeded smoothly to give the desired product 2j in 72% yield. This result was in contrast to the result of substrate 1e, in which many side-reactions occurred and no desired product was observed due to the competitive reactions occurring on the electron-rich aryl ring. The successful outcome of substrate 1j illustrated that the p-OMe-phenyl substituent of the alkyne helped stabilizing the chloronium ion intermediate (A, Scheme 2) which eventually led to the desired product 2j. For substrates 1k and 1l containing R² = p-F- and p-Cl-phenyl groups, the reactions afforded the desired 4-chloroisoxazole products 2k and 2l in 71% and 95% yields, respectively. Additionally, our method was applicable for the synthesis of other 4-haloisoxazole derivatives, requiring appropriate N-halosuccinimides. Thus, (Z)-alkynyl-O-methyl oxime 1a could be conveniently transformed in good to excellent yields to both 4-bromoisoxazole 2a-Br (80%) and 4-iodoisoxazole 2a-I (85%).

We next tested our hypothesis that our protocol could isomerize (E)-alkynyl-O-methyl oximes and then cyclize to the desired 4-chloroisoxazoles by preparing (E)-1m,¹¹ which was the only easily accessible oxime as the pure (E)-isomer. In further optimizing the conditions, we found that an additional equivalent of TMSCl was beneficial in facilitating the isomerization of (E/Z)-isomeric substrates. We then subjected (E)-1m to 1.1 equiv. of NCS and 2.0 equiv. of TMSCl in CH₃NO₂ at rt and found that the desired isoxazole 2m-Cl could be obtained in 29% yield. The reaction of (E)-1m was also attempted with NBS, which afforded the corresponding 2m-Br in 22% yield. In both cases, side-reactions were also observed. Surprisingly, when NIS was employed in the reaction at rt for 5 h, the corresponding 2m-I was gratifyingly obtained in excellent yield (89%) with much less side-reactions. The results of these three reactions clearly supported our hypothesis that our protocol could facilitate the isomerization of the normally non-cyclizable (E)-alkynyl-O-methyl oxime to the (Z)-isomer, which could readily cyclize to the desired isoxazole products under the reaction conditions, thus enabling the preparation of 4-haloisoxazoles from both (E)- and (Z)-alkynyl-O-methyl oximes. These results also suggested that the outcome of the reactions seemed to depend on the nature of N-halosuccinimide. We next applied our protocol to mixture of (E/Z)-alkynyl-O-methyl oximes 1m (R¹ = CH₃, (E) : (Z) = 41 : 59) using NCS and NIS as shown in Table 3. In these cases, isoxazoles 2m-Cl and 2m-I were obtained in 56% and 86% yields, respectively. The scope of the substrates was further studied with starting materials 1n to 1u, which were prepared (R¹ = alkyl group, R² = Ph or alkyl group, Table 3) and obtained as mixtures of (E)- and (Z)-isomers in varying ratios, except for 1t which was obtained only as the (Z)-isomer; the results are summarized in Table 3.

With R¹ = Et, O-methyl oxime 1n ((E) : (Z) = 34 : 66) was transformed to isoxazole 2n-Cl in 68% yield. For substrates with longer 1° alkyl groups, R¹ = n-C₅H₁₁ (1o; (E) : (Z) = 20 : 80) and R¹ = n-C₁₁H₂₃ (1p; (E) : (Z) = 34 : 66), the reactions led to the corresponding products 2o-Cl and 2p in 76% and 58% yields, respectively. These results showed that longer R¹ alkyl chains could tolerate the reaction conditions well to provide the products in moderate to good yields. We then looked at R¹ = 2° alkyl groups, substrates 1q (R¹ = i-Pr; (E) : (Z) = 28 : 72), 1r (R¹ = s-Bu; (E) : (Z) = 20 : 80) and 1s (R¹ = cyclohexyl; (E) : (Z) = 20 : 80) underwent the reactions uneventfully to give isoxazoles 2q-Cl (76%), 2r (72%) and 2s-Cl (77%) in good yields. Finally, R¹ = 3° alkyl group was investigated. Thus, the reaction of O-methyl oxime 1t (R¹ = t-Bu), obtained only as (Z)-isomer, proceeded to provide the corresponding product 2t in 88% yield. In this case, the reaction, which started with only the (Z)-isomer of 1t, needed only 1.0 equiv. of TMSCl for a complete conversion to deliver the product in excellent yield. The result implied that no additional TMSCl was needed for the HCl generation to assist in the (E) → (Z) isomerization process. In the reaction of 1t, TMSCl was consumed only for the generation of Cl₂ to facilitate the cyclization, which further substantiated our hypothesis regarding the role of TMSCl. Although the yield of 2t was high, it was still inferior compared to 2a (R¹ = Ph, 99%, Table 2). These results showed the general trend of the reaction regarding yields of products as related to the effect of R¹ (with R² = Ph) as followed: Ph > 3° > 2° > 1° > CH₃. Finally, the substrate with both R¹ = R² = alkyl groups was studied in compound 1u (R¹ = n-C₅H₁₁, R² = n-C₄H₉, (E) : (Z) = 32 : 68) which was transformed to 4-chloroisoxazole 2u-Cl in 47% yield. This latter result also showed the general trend in yields of products related to R¹ and R² as followed: R¹ = R² = aryl > R¹ = alkyl, R² = aryl > R¹ = R² = alkyl.

The yields of 4-chloroisoxazoles 2n-Cl (68%) and 2q-Cl (76%) in Table 3 further proved that the (E)-alkynyl-O-methyl oximes in the mixtures of substrates 1n and 1q were isomerized and cyclized to the desired products since the yields obtained for each case were higher than the proportions of (Z)-isomer in the starting materials. As exemplified with alkynyl-O-methyl oxime 1m, our method was applied to prepare 4-bromo- and 4-iodoisoxazoles from other alkynyl-O-methyl oximes. As shown in Table 3, alkynyl-O-methyl oxime 1n ((E) : (Z) = 34 : 66) was converted to the corresponding 4-bromoisoxazole 2n-Br in 74% yield while alkynyl-O-methyl oxime 1o ((E) : (Z) = 20 : 80) was also converted smoothly to product 1o-Br in 81% yield. Similarly, compound 1q ((E) : (Z) = 28 : 72) underwent the reaction to the corresponding 4-bromoisoxazole (2q-Br) in 89% yield. In case of compound 1s ((E) : (Z) = 25 : 75), the reaction produced the desired product (2s-Br) in 78% yield. Finally, for substrate 1u ((E) : (Z) = 32 : 68), the reactions with NBS and NIS produced the corresponding products 2u-Br and 2u-I in 60% and 55% yields, respectively. Among these cases, yields of products 2m-Cl, (from (E/Z)-1m), 2o-Cl, 2p, 2r, 2s-Cl, 2u-Br and 2u-I were slightly lower than the proportions of the (Z)-isomers present in the starting materials. However, as the conversions of the (Z)-starting materials could not always be quantitative, it could be implicated that the (E)-isomers could isomerize and cyclize, thus contributing to the overall yields of products. Moreover, the isomerization-cyclization process of the (E)-isomers could be supported by the yields of products 2n-Cl, 2q-Cl, 2n-Br, 2o-Br, 2q-Br, 2s-Br and 2m-I (from (E/Z)-1m) as they were greater than or equal to the proportions of the (Z)-isomers present in the starting materials. The strongest cases to support such isomerization process were demonstrated in the reactions of pure (E)-1m which gave isoxazoles 2m-Cl, 2m-Br and 2m-I in 29%, 22% and 89% yields, respectively (Table 3).

Conclusions

We have developed the first method for the direct conversion of alkynyl-O-methyl oximes to 4-chloroisoxazoles via chlorinative cyclization. This is also the first method which could be employed for both (E)- and (Z)-alkynyl-O-methyl oximes. This is due to the fact that the unreactive (E)-isomers can be isomerized and cyclized under the reaction conditions. The current method therefore constitutes a protocol having higher efficiency than the previous methods, and can be employed for mixtures of both (E/Z)-alkynyl-O-methyl oximes. The protocol conveniently employs the combination of TMSCl and NCS in nitromethane at room temperature, which produces Cl₂ and HCl in situ to promote the cyclization to furnish 4-chloroisoxazole products in moderate to excellent yields. This method is effectively applicable to a broad range of substrates and is also appropriate for the preparation of 4-bromo- and 4-iodoisoxazole derivatives simply by using NBS and NIS instead of NCS.

Experimental

General procedure

Commercial grade chemicals were used without further purification, unless otherwise specified. All solvents were used as received. Oven-dried glassware (110 °C at least for 2 h) was used for all reactions. Crude reaction mixtures were concentrated under reduced pressure on a rotary evaporator. Column chromatography was performed using silica gel 60 (particle size 0.06–0.2 mm; 70–230 mesh ASTM). Analytical thin-layer chromatography (TLC) was performed with silica gel 60 F₂₅₄ aluminum sheets. Nuclear magnetic resonance (NMR) spectra were recorded in deuterochloroform (CDCl₃) or dimethyl sulfoxide-d₆ (DMSO-d₆) with 300 and 600 MHz spectrometers. Chemical shifts for ¹H NMR and ¹³C NMR spectra are reported in parts per million (ppm, δ), relative to tetramethylsilane (TMS) as the internal reference. Coupling constants (J) are reported in hertz (Hz). Infrared spectra were measured using an FT-IR spectrometer and are reported in cm⁻¹. High-resolution mass spectra (HRMS) were obtained using a time-of-flight (TOF) instrument.

General procedure for the preparation of (Z)-alkynyl-O-methyl oximes 1a–u

The solution of 1,3-diphenylprop-2-yn-1-one (561.2 mg, 2.72 mmol, 1.0 equiv.) in MeOH (12.0 mL, 4.5 mL mmol⁻¹) was added sequentially with MeONH₂·HCl (469.6 mg, 5.44 mmol, 2.0 equiv.), Na₂SO₄ (864.3 mg, 5.44 mmol, 2.0 equiv.), and pyridine (1.2 mL, 14.9 mmol, 5.5 equiv.). The resulting reaction mixture was stirred overnight and quenched by addition of water. The mixture was then extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous MgSO₄ and concentrated on a rotary evaporator. The crude product was purified by SiO₂ column chromatography (2% EtOAc–hexane) to afford (Z)-1,3-diphenylprop-2-yn-1-one O-methyl oxime (1a) (340.3 mg, 53%).

(Z)-1,3-Diphenylprop-2-yn-1-one O-methyl oxime (1a)^5b. Yield 340.3 mg (53%, white solid); mp 44.9–45.1 °C; IR (neat): ν_max 3058, 2936, 2820, 2213, 1444, 1337, 1048 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.00–7.97 (m, 2H), 7.68–7.65 (m, 2H), 7.47–7.39 (m, 6H), 4.19 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 139.8, 133.5, 132.1, 129.6, 129.5, 128.38, 128.36, 126.4, 121.7, 101.1, 79.4, 63.0; HRMS (ESI) calcd for C₁₆H₁₄NO (M + H)⁺ 236.1070, found 236.1060.

(E)-3-Phenyl-1-(o-tolyl)prop-2-yn-1-one O-methyl oxime (1b)^5b. Yield 17.5 mg (14%, yellow oil); IR (neat): ν_max 3749, 3058, 2934, 2818, 1689, 1046, 758 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.48–7.45 (m, 3H), 7.31–7.15 (m, 6H), 4.05 (s, 3H), 2.47 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 140.8, 136.8, 133.4, 132.1, 131.0, 129.5, 129.4, 129.1, 128.4, 125.9, 121.8, 101.2, 80.7, 63.0, 20.8; HRMS (ESI) calcd for C₁₇H₁₆NO (M + H)⁺ 250.1226, found 250.1235.

(Z)-1-([1,1′-Biphenyl]-4-yl)-3-phenylprop-2-yn-1-one O-methyl oxime (1c). Yield 105.5 mg (40%, white solid); mp 111.7–112.1 °C; IR (neat): ν_max 3364, 2923, 2852, 2349, 2216, 1047 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.00–7.97 (m, 2H), 7.66–7.62 (m, 6H), 7.48–7.37 (m, 6H), 4.16 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 142.4, 140.4, 139.6, 132.5, 132.1, 129.5, 128.8, 128.4, 127.6, 127.1, 127.0, 126.9, 121.7, 101.2, 79.4, 63.1; HRMS (ESI) calcd for C₂₂H₁₈NO (M + H)⁺ 312.1383, found 312.1374.

(E)-1-([1,1′-Biphenyl]-2-yl)-3-phenylprop-2-yn-1-one O-methyl oxime (1d). Yield 100.2 mg (28%, colorless oil); IR (neat): ν_max 3059, 2935, 2210, 1951, 1443, 1044, 748 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.58–7.55 (m, 1H), 7.42–7.28 (m, 7H), 7.24–7.10 (m, 4H), 7.06–7.03 (m, 2H), 3.97 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 141.5, 141.3, 140.9, 133.0, 131.9, 130.6, 129.7, 129.5, 129.4, 129.1, 128.2, 128.0, 127.4, 127.1, 121.6, 101.5, 80.5, 62.9; HRMS (ESI) calcd for C₂₂H₁₈NO (M + H)⁺ 312.1383, found 312.1384.

(Z)-1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-one O-methyl oxime (1e)¹². Yield 279.1 mg (63%, white solid); mp 63.2–63.4 °C; IR (neat): ν_max 2935, 2899, 2838, 2213, 1944, 1606, 1047 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.90–7.85 (m, 2H), 7.64–7.61 (m, 2H), 7.42–7.35 (m, 3H), 6.96–6.91 (m, 2H), 4.13 (s, 3H), 3.84 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 160.9, 139.5, 132.1, 129.4, 128.4, 127.9, 126.2, 121.8, 113.8, 100.8, 79.5, 62.9, 55.3; HRMS (ESI) calcd for C₁₇H₁₆NO₂ (M + H)⁺ 266.1176, found 266.1179.

(Z)-1-(4-Fluorophenyl)-3-phenylprop-2-yn-1-one O-methyl oxime (1f)^4a. Yield 72.8 mg (26%, yellow oil); IR (neat): ν_max 2937, 2901, 2214, 1602, 1046 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.92–7.87 (m, 2H), 7.62–7.59 (m, 2H), 7.39–7.33 (m, 3H), 7.10–7.05 (m, 2H), 4.12 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 163.7 (d, J_C–F = 248 Hz), 138.8, 132.1, 129.7 (d, J_C–F = 3 Hz), 129.6, 128.4 (d, J_C–F = 5 Hz), 128.3, 121.6, 115.4 (d, J_C–F = 22 Hz), 101.3, 79.2, 63.1; HRMS (ESI) calcd for C₁₆H₁₃FNO (M + H)⁺ 254.0976, found 254.0973.

(Z)-1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-one O-methyl oxime (1g)^5b. Yield 80.1 mg (30%, colorless oil); IR (neat): ν_max 2935, 2891, 2213, 1489, 1050 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.85 (d, J = 8.7 Hz, 2H), 7.62–7.59 (m, 2H), 7.42–7.35 (m, 5H), 4.13 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 138.9, 135.7, 132.2, 132.1, 129.7, 128.6, 128.5, 127.7, 121.6, 101.5, 79.0, 63.2; HRMS (ESI) calcd for C₁₆H₁₃ClNO (M + H)⁺ (Cl-35) 270.0680, found 270.0668.

(Z)-1-(3-Chlorophenyl)-3-phenylprop-2-yn-1-one O-methyl oxime (1h). Yield 59.1 mg (28%, colorless oil); IR (neat): ν_max 3063, 2937, 2818, 2217, 1594, 1328, 1043, 821, 756 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.93 (s, 1H), 7.81 (dd, J = 7.2, 1.8 Hz, 1H), 7.65–7.62 (m, 2H), 7.44–7.31 (m, 5H), 4.16 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 138.6, 135.3, 134.4, 132.1, 129.7, 129.60, 129.58, 128.4, 126.3, 124.7, 121.5, 101.6, 78.9, 63.3; HRMS (ESI) calcd for C₁₆H₁₃ClNO (M + H)⁺ (Cl-35) 270.0680, found 270.0683.

(Z)-1-(4-Bromophenyl)-3-phenylprop-2-yn-1-one O-methyl oxime (1i). Yield 97.0 mg (24%, colorless oil); IR (neat): ν_max 2925, 2853, 2370, 2213, 1053 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.83–7.79 (m, 2H), 7.64–7.52 (m, 4H), 7.45–7.36 (m, 3H), 4.15 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 138.9, 132.5, 132.1, 131.5, 129.6, 128.4, 127.9, 123.9, 121.5, 101.5, 78.9, 63.2; HRMS (ESI) calcd for C₁₆H₁₃BrNO (M + H)⁺ (Br-79) 314.0175, found 314.0170.

(Z)-3-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-one O-methyl oxime (1j)^5b. Yield 82.0 mg (52%, colorless oil); IR (neat): ν_max 3058, 2962, 2935, 2837, 2208, 1604, 1249, 1042 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.94–7.91 (m, 2H), 7.60–7.55 (m, 2H), 7.43–7.38 (m, 3H), 6.93–6.88 (m, 2H), 4.15 (s, 3H), 3.84 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 160.6, 140.1, 133.8, 133.7, 129.6, 128.3, 126.5, 114.1, 113.7, 101.6, 78.6, 63.0, 55.3; HRMS (ESI) calcd for C₁₇H₁₅NNaO₂ (M + Na)⁺ 288.0995, found 288.0996.

(Z)-3-(4-Fluorophenyl)-1-phenylprop-2-yn-1-one O-methyl oxime (1k). Yield 133.4 mg (54%, colorless oil); IR (neat): ν_max 3449, 2938, 2213, 1506, 1234, 1048, 836, 692 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.96–7.93 (m, 2H), 7.66–7.59 (m, 2H), 7.45–7.40 (m, 3H), 7.13–7.05 (m, 2H), 4.17 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 163.2 (d, J_C–F = 250 Hz), 139.7, 134.1 (d, J_C–F = 9 Hz), 133.4, 129.7, 128.4, 126.4, 117.8 (d, J_C–F = 4 Hz), 115.8 (d, J_C–F = 22 Hz), 100.0, 79.2, 63.0; HRMS (ESI) calcd for C₁₆H₁₃NOF (M + H)⁺ 254.0976, found 254.0975.

(Z)-3-(4-Chlorophenyl)-1-phenylprop-2-yn-1-one O-methyl oxime (1l)¹³. Yield 63.2 mg (34%, colorless oil); IR (neat): ν_max 3455, 2071, 1638, 1335, 828 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.93–7.91 (m, 2H), 7.57–7.54 (m, 2H), 7.43–7.36 (m, 5H), 4.16 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 139.6, 135.7, 133.3, 129.7, 128.8, 128.4, 126.4, 120.2, 99.8, 80.3, 63.1; HRMS (ESI) calcd for C₁₆H₁₃ClNO (M + H)⁺ (Cl-35) 270.0680, found 270.0686.

4-Phenylbut-3-yn-2-one O-methyl oxime (1m)^5b. Yield 157.4 mg (69%, (E) : (Z) = 41 : 59, colorless oil); IR (neat): ν_max 3580, 2925, 2855, 2309, 1731, 1462, 1262 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.54–7.49 (m, 2H), 7.40–7.29 (m, 3H), 3.98 (s, 2.11H, minor), 3.97 (s, 3H), 2.13 (s, 3H), 2.09 (s, 2.11H, minor); ¹³C NMR (75 MHz, CDCl₃) δ 142.1 (minor), 137.2, 131.9, 131.7 (minor), 129.2, 128.8 (minor), 128.2, 121.8 (minor), 121.5, 98.9, 90.0 (minor), 85.4 (minor), 80.9, 62.2 (minor), 62.0, 20.4, 16.4 (minor); HRMS (ESI) calcd for C₁₁H₁₂NO (M + H)⁺ 174.0913, found 174.0917.

(E)-4-Phenylbut-3-yn-2-one O-methyl oxime (1m)^5b. Yield 81.9 mg (22%, colorless oil); ¹H NMR (300 MHz, CDCl₃) δ 7.52–7.49 (m, 2H), 7.34–7.29 (m, 3H), 3.98 (s, 3H), 2.08 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 142.3, 131.9, 129.0, 128.3, 121.9, 90.1, 85.4, 62.4, 16.6; HRMS (ESI) calcd for C₁₁H₁₂NO (M + H)⁺ 174.0913, found 174.0917.

1-Phenylpent-1-yn-3-one O-methyl oxime (1n). Yield 126.2 mg (73%, (E) : (Z) = 34 : 66, colorless oil); IR (neat): ν_max 3559, 3058, 2927, 2851, 2370, 1947, 1725, 1265, 1095 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.54–7.51 (m, 2H), 7.39–7.32 (m, 3H), 3.98 (s, 3H), 2.52 (q, J = 7.8 Hz, 1.02H, minor), 2.44 (q, J = 7.8 Hz, 2H), 1.25–1.20 (m, 3H); ¹H NMR (300 MHz, CDCl₃) δ 7.57–7.52 (m, 2H), 7.43–7.33 (m, 3H), 3.99 (s, 3H), 2.53 (q, J = 7.5 Hz, 1.02H, minor), 2.45 (q, J = 7.8 Hz, 2H), 1.28–1.20 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 148.0, 142.7, 131.9, 131.8, 129.2, 128.8, 128.2, 121.9, 121.6, 99.5, 91.3, 84.0, 80.0, 62.3, 62.1, 27.8, 22.5, 11.6, 10.3; HRMS (ESI) calcd for C₁₂H₁₃NNaO (M + Na)⁺ 210.0889, found 210.0879.

(Z)-1-Phenyloct-1-yn-3-one O-methyl oxime (1o). Yield 145.4 mg (97%, (E) : (Z) = 20 : 80, yellow oil); IR (neat): ν_max 3902, 3750, 2957, 2930, 2858, 1048 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.55–7.48 (m, 2H), 7.38–7.31 (m, 3H), 3.972 (s, 3H), 3.965 (s, 0.74H, minor), 2.49 (t, J = 7.5 Hz, 0.49H, minor), 2.40 (t, J = 7.5 Hz, 2H), 1.73–1.63 (m, 2H), 1.39–1.33 (m, 4H), 0.93–0.89 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 147.1, 141.9, 132.0, 131.8, 129.2, 128.9, 128.3, 122.0, 121.7, 99.4, 90.9, 84.5, 80.3, 62.3, 62.1, 34.2, 31.4, 31.0, 29.1, 26.7, 25.5, 22.3, 13.9; HRMS (ESI) calcd for C₁₅H₂₀NO (M + H)⁺ 230.1539, found 230.1549.

1-Phenyltetradec-1-yn-3-one O-methyl oxime (1p). Yield 206.1 mg (65%, (E) : (Z) = 34 : 66, dark brown oil); IR (neat): ν_max 2925, 2854, 2208, 1464, 1047, 755 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.54–7.48 (m, 2H), 7.38–7.30 (m, 3H), 3.96 (s, 3H), 2.49 (t, J = 7.5 Hz, 1.04H, minor), 2.39 (t, J = 7.5 Hz, 2H), 1.72–1.60 (m, 2H), 1.33–1.26 (m, 16H), 0.88 (t, J = 6.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 147.2, 142.0, 132.1, 131.9, 129.3, 128.9, 128.3, 122.1, 121.8, 99.5, 91.0, 84.5, 80.3, 62.3, 62.2, 34.3, 31.9, 29.6, 29.5, 29.30, 29.27, 28.9, 27.0, 25.9, 22.6, 14.1; HRMS (ESI) calcd for C₂₁H₃₂NO (M + H)⁺ 314.2478, found 314.2487.

4-Methyl-1-phenylpent-1-yn-3-one O-methyl oxime (1q). Yield 502.0 mg (92%, (E) : (Z) = 28 : 72, light yellow oil); IR (neat): ν_max 2968, 2936, 2213, 1444, 1034, 755 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.55–7.50 (m, 2H), 7.40–7.30 (m, 3H), 3.96 (s, 3H), 3.40 (sept, J = 6.9 Hz, 0.38H, minor), 2.73 (sept, J = 6.9 Hz, 1H), 1.23 (d, J = 6.9 Hz, 6H), 1.16 (d, J = 6.9 Hz, 2.28H, minor); ¹³C NMR (75 MHz, CDCl₃) δ 152.4, 146.8, 132.0, 131.8, 129.2, 128.8, 128.2, 122.0, 121.8, 100.1, 92.0, 82.4, 78.8, 62.2, 62.0, 33.3, 26.8, 20.4, 19.4; HRMS (ESI) calcd for C₁₃H₁₆NO (M + H)⁺ 202.1226, found 202.1229.

4-Methyl-1-phenylhex-1-yn-3-one O-methyl oxime (1r). Yield 194.5 mg (89%, (E) : (Z) = 20 : 80, yellow oil); IR (neat): ν_max 3525, 2965, 2934, 2876, 2210, 1457, 1041, 755, 689 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.55–7.49 (m, 2H), 7.40–7.31 (m, 3H), 3.97 (s, 3H), 3.95 (s, 0.75H, minor), 3.24 (sex, J = 6.6 Hz, 0.25H, minor), 2.48 (sex, J = 6.9 Hz, 1H), 1.77–1.41 (m, 2H), 1.21 (d, J = 6.6 Hz, 3H), 1.14 (d, J = 6.9 Hz, 0.75H, minor), 0.94 (t, J = 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 151.8, 146.2, 132.1, 131.9, 129.2, 128.8, 128.3, 122.1, 121.8, 100.0, 91.6, 82.6, 78.8, 62.2, 62.1, 40.2, 33.7, 27.6, 27.2, 18.4, 17.4, 11.8, 11.7; HRMS (ESI) calcd for C₁₄H₁₈NO (M + H)⁺ 216.1383, found 216.1390.

1-Cyclohexyl-3-phenylprop-2-yn-1-one O-methyl oxime (1s). Yield 427.2 mg (87%, (E) : (Z) = 20 : 80, yellow oil); IR (neat): ν_max 2929, 2854, 2817, 2217, 1574, 1444, 1044, 754, 689 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.55–7.50 (m, 2H), 7.38–7.31 (m, 3H), 3.964 (s, 3H), 3.956 (s, 0.73H), 3.10 (tt, J = 11.7, 3.0 Hz, 0.24H, minor), 2.41 (tt, J = 11.7, 3.3 Hz, 1H), 1.90–1.15 (m, 10H); ¹³C NMR (75 MHz, CDCl₃) δ 151.5, 146.2, 132.0, 131.8, 129.2, 128.8, 128.2, 122.1, 121.8, 100.0, 91.7, 83.2, 79.4, 62.3, 62.1, 42.9, 36.8, 30.6, 29.4, 25.8, 25.7, 25.6; HRMS (ESI) calcd for C₁₆H₂₀NO (M + H)⁺ 242.1539, found 242.1543.

(Z)-4,4-Dimethyl-1-phenylpent-1-yn-3-one O-methyl oxime (1t)^5a. Yield 379.2 mg (90%, dark brown oil); IR (neat): ν_max 2968, 2931, 2818, 2215, 1363, 1051, 755, 690 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.55–7.52 (m, 2H), 7.40–7.31 (m, 3H), 3.97 (s, 3H), 1.26 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 149.1, 132.0, 129.1, 128.3, 122.0, 100.3, 79.3, 62.2, 36.9, 28.2; HRMS (ESI) calcd for C₁₄H₁₈NO (M + H)⁺ 216.1383, found 216.1389.

Dodec-7-yn-6-one O-methyl oxime (1u). Yield 281.9 mg (80%, (E) : (Z) = 32 : 68, colorless oil); IR (neat): ν_max 2957, 2928, 2856, 2349, 1821, 1739, 1457, 1053, 799 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 3.91 (s, 3H), 3.89 (s, 1.42H, minor), 2.43 (t, J = 7.2 Hz, 2H), 2.38–2.34 (m, 1.95H, minor), 2.27 (t, J = 7.2 Hz, 2H), 1.62–1.52 (m, 4H), 1.48–1.42 (m, 2H), 1.36–1.28 (m, 4H), 0.94–0.89 (m, 6H); ¹H NMR (300 MHz, CDCl₃) δ 3.91 (s, 3H), 3.89 (s, 1.42H, minor), 2.44 (t, J = 6.9 Hz, 2H), 2.39–2.33 (m, 1.95H, minor), 2.24 (t, J = 7.8 Hz, 2H), 1.62–1.26 (m, 10H), 0.95–0.87 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 147.2, 142.2, 102.0, 92.6, 75.9, 72.3, 61.8, 34.3, 31.3, 30.9, 30.2, 29.0, 26.5, 25.4, 22.2, 21.81, 21.77, 19.1, 18.8, 13.7, 13.3; HRMS (ESI) calcd for C₁₃H₂₄NO (M + H)⁺ 210.1852, found 210.1857.

General procedure for the synthesis of 4-haloisoxazoles 2a–l (Table 2) and 2t (Table 3)

To the solution of (Z)-alkynyl-O-methyl oxime 1a (71.1 mg, 0.30 mmol, 1.0 equiv.) in nitromethane (3.0 mL, 10.0 mL mmol⁻¹) was added with NCS (45.8 mg, 0.33 mmol, 1.1 equiv.), followed by TMSCl (38.4 μL, 0.30 mmol, 1.0 equiv.). The reaction was monitored by TLC until completion. It was then diluted with water and extracted with EtOAc, dried over anhydrous MgSO₄ and concentrated on a rotary evaporator. The crude product was purified by SiO₂ column chromatography (10% EtOAc–hexane) to afford 4-chloro-3,5-diphenylisoxazole (2a-Cl) (76.5 mg, ≥99%).

General procedure for the synthesis of 4-haloisoxazoles 2m–u (Table 3, except 2t)

To the solution of alkynyl-O-methyl oxime 1m ((E) : (Z) = 41 : 59) (62.3 mg, 0.36 mmol, 1.0 equiv.) in nitromethane (3.6 mL, 10.0 mL mmol⁻¹) was added with NCS (52.8 mg, 0.40 mmol, 1.1 equiv.), followed by TMSCl (91.0 μL, 0.72 mmol, 2.0 equiv.). The reaction was monitored by TLC until completion. It was then diluted with water and extracted with EtOAc, dried over anhydrous MgSO₄ and concentrated on a rotary evaporator. The crude product was purified by SiO₂ column chromatography (2% EtOAc–hexane) to afford 4-chloro-3-methyl-5-phenylisoxazole (2m) (39.1 mg, 56%).

4-Chloro-3,5-diphenylisoxazole (2a-Cl)^6a. Yield 76.5 mg (≥99%, white solid); mp 65.7–65.9 °C; IR (neat): ν_max 3055, 2923, 2853, 1492, 1459, 1448, 1397, 1127, 767, 706, 690 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ 8.02–7.99 (m, 2H), 7.86–7.80 (m, 2H), 7.65–7.57 (m, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ 163.8, 160.4, 131.2, 130.7, 129.4, 129.1, 128.1, 126.6, 126.4, 125.5, 104.2; HRMS (ESI) calcd for C₁₅H₁₁ClNO (M + H)⁺ (Cl-35) 256.0524, found 256.0517.

4-Bromo-3,5-diphenylisoxazole (2a-Br)^5b. Yield 88.9 mg (80%, yellow solid); mp 126.1–126.5 °C; IR (neat): ν_max 3449, 3053, 1613, 1447, 1115, 692 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.12–8.08 (m, 2H), 7.89–7.86 (m, 2H), 7.54–7.52 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 165.8, 162.1, 130.7, 130.2, 128.8, 128.63, 128.58, 127.8, 127.0, 126.8, 89.5; HRMS (ESI) calcd for C₁₅H₁₁NOBr (M + H)⁺ (Br-79) 300.0019, found 300.0010.

4-Iodo-3,5-diphenylisoxazole (2a-I)^5b. Yield 103.8 mg (85%, white solid); mp 161.4–161.6 °C; IR (neat): ν_max 3457, 2069, 1638, 1446, 765 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ 8.04–8.00 (m, 2H), 7.76–7.72 (m, 2H), 7.66–7.57 (m, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ 168.6, 164.8, 131.0, 130.3, 129.2, 128.84, 128.80, 128.5, 127.6, 126.9, 59.5; HRMS (ESI) calcd for C₁₅H₁₁INO (M + H)⁺ (I-127) 347.9880, found 347.9877.

4-Chloro-5-phenyl-3-(o-tolyl)isoxazole (2b). Yield 64.9 mg (83%, colorless oil); IR (neat): ν_max 3611, 3063, 2925, 2854, 1448, 1389, 767, 689 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ 8.04–8.01 (m, 2H), 7.65–7.57 (m, 3H), 7.50–7.34 (m, 4H), 2.28 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 162.9, 162.0, 137.1, 131.2, 130.6, 130.4, 129.9, 129.4, 126.2, 126.1, 125.9, 125.6, 105.4, 19.4; HRMS (ESI) calcd for C₁₆H₁₃ClNO (M + H)⁺ (Cl-35) 270.0680, found 270.0690.

3-([1,1′-Biphenyl]-4-yl)-4-chloro-5-phenylisoxazole (2c). Yield 47.8 mg (69%, white solid); mp 136.3–136.7 °C; IR (neat): ν_max 3453, 3058, 2921, 2851, 2126, 1420, 768, 730 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.01–7.98 (m, 2H), 7.93–7.90 (m, 2H), 7.69–7.64 (m, 2H), 7.59–7.55 (m, 2H), 7.49–7.37 (m, 5H), 7.31 (tt, J = 7.2, 1.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 164.2, 160.4, 143.1, 140.2, 130.6, 128.9, 128.6, 127.8, 127.4, 127.2, 126.6, 126.5, 126.3, 104.6; HRMS (ESI) calcd for C₂₁H₁₅ClNO (M + H)⁺ (Cl-35) 332.0837, found 332.0842.

3-([1,1′-Biphenyl]-2-yl)-4-chloro-5-phenylisoxazole (2d). Yield 63.0 mg (59% as a colorless oil). IR (neat): ν_max 3060, 3027, 1591, 1447, 1391, 1129, 766, 742 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 7.95–7.92 (m, 2H), 7.63–7.43 (m, 7H), 7.34–7.24 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 163.2, 162.8, 142.2, 140.1, 130.9, 130.42, 130.36, 129.2, 128.8, 128.1, 127.3, 126.4, 126.2, 125.5, 106.2; HRMS (ESI) calcd for C₂₁H₁₅ClNO (M + H)⁺ (Cl-35) 332.0837, found 332.0833.

(9Z)-10-(Chloro(phenyl)methylene)phenanthren-9(10H)-one O-methyl oxime (3d). Yield 27.6 mg (25%, yellow solid); mp 159.7–161.2 °C; IR (neat): ν_max 3059, 2935, 2819, 1935, 1599, 1442, 1051, 767, 736, 700 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.68 (d, J = 7.5 Hz, 1H), 7.59–7.40 (m, 4H), 7.33–7.11 (m, 7H), 6.96 (d, J = 8.1 Hz, 1H), 3.96 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 152.0, 139.5, 139.1, 137.9, 137.8, 137.6, 136.3, 131.3, 130.7, 130.3, 130.1, 129.5, 129.2, 128.2, 128.1, 127.9, 127.7, 127.0, 126.9, 121.0, 62.9; HRMS (ESI) calcd for C₂₂H₁₇ClNO (M + H)⁺ (Cl-35) 346.0993, found 346.0986.

4-Chloro-3-(4-fluorophenyl)-5-phenylisoxazole (2f). Yield 69.3 mg (88%, white solid); mp 89.9–90.4 °C; IR (neat): ν_max 3053, 1902, 1607, 1127, 840 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.07–8.04 (m, 2H), 7.93–7.88 (m, 2H), 7.56–7.51 (m, 3H), 7.26–7.18 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 164.0 (d, J_C–F = 249 Hz), 164.3, 159.9, 130.7, 130.3 (d, J_C–F = 8 Hz), 128.9, 126.6, 126.4, 123.6 (d, J_C–F = 3 Hz), 115.9 (d, J_C–F = 22 Hz), 104.4; ESI-HRMS calcd for C₁₅H₁₀ClFNO (M + H)⁺ (Cl-35) 274.0430, found 274.0419.

4-Chloro-3-(4-chlorophenyl)-5-phenylisoxazole (2g). Yield 103.2 mg (75%, white solid); mp 92.3–93.5 °C; IR (neat): ν_max 3357, 3063, 2924, 2854, 2349, 1603, 1419 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.06–8.02 (m, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.56–7.47 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 164.4, 159.7, 136.5, 130.7, 129.5, 129.0, 128.9, 126.5, 126.3, 125.8, 104.4; HRMS (ESI) calcd for C₁₅H₁₀Cl₂NO (M + H)⁺ (Cl-35) 290.0134, found 290.0138.

4-Chloro-3-(3-chlorophenyl)-5-phenylisoxazole (2h). Yield 83.4 mg (96%, white solid); mp 86.6–86.8 °C; IR (neat): ν_max 3059, 2936, 2326, 1439, 1378, 775 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.07–8.04 (m, 2H), 7.92–7.91 (m, 1H), 7.82–7.79 (m, 1H), 7.57–7.42 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 164.4, 159.5, 134.7, 130.7, 130.3, 130.0, 129.0, 128.9, 128.2, 126.5, 126.3, 126.2, 104.4; HRMS (ESI) calcd for C₁₅H₁₀Cl₂NO (M + H)⁺ (Cl-35) 290.0134, found 290.0126.

3-(4-Bromophenyl)-4-chloro-5-phenylisoxazole (2i). Yield 23.4 mg (70%, white solid); mp 109.0–109.3 °C; IR (neat): ν_max 3504, 2127, 1985, 1924, 1640, 830 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.07–8.04 (m, 2H), 7.81–7.78 (m, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.57–7.50 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 164.4, 159.8, 132.0, 130.7, 129.7, 128.9, 126.5, 126.30, 126.27, 124.9, 104.3; HRMS (ESI) calcd for C₁₅H₁₀BrClNO (M + H)⁺ (Cl-35) (Br-79) 333.9629, found 333.9637.

4-Chloro-5-(4-methoxyphenyl)-3-phenylisoxazole (2j). Yield 51.2 mg (72%, white solid); mp 97.5–97.8 °C; IR (neat): ν_max 3160, 3068, 2952, 2846, 1773, 1694, 1189, 833, 687 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.04–8.00 (m, 2H), 7.90–7.87 (m, 2H), 7.52–7.50 (m, 3H), 7.06–7.02 (m, 2H), 3.88 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 164.1, 161.3, 160.6, 130.2, 128.7, 128.21, 128.16, 127.5, 119.2, 114.3, 103.1, 55.4; HRMS (ESI) calcd for C₁₆H₁₃ClNO₂ (M + H)⁺ (Cl-35) 286.0629, found 286.0627.

4-Chloro-5-(4-fluorophenyl)-3-phenylisoxazole (2k). Yield 50.3 mg (71%, white solid); mp 94.8–95.0 °C; IR (neat): ν_max 3451, 2134, 2030, 1638, 1239, 837 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.09–8.04 (m, 2H), 7.90–7.87 (m, 2H), 7.53–7.51 (m, 3H), 7.26–7.18 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 163.9 (d, J_C–F = 251 Hz), 163.3, 160.8, 130.4, 128.80, 128.78 (d, J_C–F = 9 Hz), 128.3, 127.3, 122.8 (d, J_C–F = 3 Hz), 116.2 (d, J_C–F = 22 Hz), 104.4; HRMS (ESI) calcd for C₁₅H₁₀ClFNO (M + H)⁺ (Cl-35) 274.0430, found 274.0439.

4-Chloro-5-(4-chlorophenyl)-3-phenylisoxazole (2l). Yield 52.1 mg (95%, white solid); mp 105.9–106.1 °C; IR (neat): ν_max 3463, 3068, 2344, 2127, 1131, 834, 696 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.94–7.90 (m, 2H), 7.82–7.77 (m, 2H), 7.46–7.39 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 163.0, 160.8, 136.7, 130.3, 129.2, 128.8, 128.2, 127.7, 127.2, 124.9, 104.9; HRMS (ESI) calcd for C₁₅H₁₀Cl₂NO (M + H)⁺ (Cl-35) 290.0134, found 290.0130.

4-Chloro-3-methyl-5-phenylisoxazole (2m-Cl)¹⁴. Yield 39.1 mg (56%, white solid); mp 35.7–36.2 °C; IR (neat): ν_max 3749, 3610, 2930, 2152, 1699, 1409, 767, 688 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.00–7.96 (m, 2H), 7.51–7.45 (m, 3H), 2.33 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 162.4, 159.4, 130.3, 128.8, 126.5, 126.1, 105.8, 9.8; HRMS (ESI) calcd for C₁₀H₉ClNO (M + H)⁺ (Cl-35) 194.0367, found 194.0363.

4-Bromo-3-methyl-5-phenylisoxazole (2m-Br)¹⁵. Yield 12.0 mg (22%, yellow oil); ¹H NMR (300 MHz, CDCl₃) δ 8.05–8.01 (m, 2H), 7.52–7.47 (m, 3H), 2.35 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 164.2, 160.6, 130.4, 128.8, 127.9, 126.8, 126.6, 91.1, 10.8.

4-Iodo-3-methyl-5-phenylisoxazole (2m-I)^5b. Yield 50.7 mg (89%, yellow oil); IR (neat): ν_max 3058, 2936, 2820, 2213, 1444, 1337, 1048 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ 7.99–7.96 (m, 2H), 7.61–7.56 (m, 3H), 2.28 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 166.7, 163.2, 130.8, 129.2, 127.0, 126.9, 60.9, 12.3; HRMS (ESI) calcd for C₁₀H₉INO (M + H)⁺ (I-131) 285.9723, found 285.9723.

4-Chloro-3-ethyl-5-phenylisoxazole (2n-Cl). Yield 70.7 mg (68%, colorless oil); IR (neat): ν_max 3062, 2979, 2939, 1713, 1594, 1448, 1072, 940, 767 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.01–7.98 (m, 2H), 7.54–7.47 (m, 3H), 2.76 (q, J = 7.8 Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 163.8, 162.6, 130.3, 128.8, 126.6, 126.3, 105.2, 18.4, 11.4; HRMS (ESI) calcd for C₁₁H₁₁ClNO (M + H)⁺ (Cl-35) 208.0524, found 208.0515.

4-Bromo-3-ethyl-5-phenylisoxazole (2n-Br). Yield 74.1 mg (74%, colorless oil); IR (neat): ν_max 3063, 2978, 2939, 1573, 1412, 1063, 689 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.04–8.01 (m, 2H), 7.54–7.48 (m, 3H), 2.75 (q, J = 7.5 Hz, 2H), 1.36 (t, J = 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 164.8, 164.3, 130.4, 128.8, 126.8, 126.7, 90.4, 19.2, 11.5; HRMS (ESI) calcd for C₁₁H₁₁BrNO (M + H)⁺ (Br-79) 252.0019, found 252.0029.

4-Chloro-3-pentyl-5-phenylisoxazole (2o-Cl). Yield 64.1 mg (76%, yellow oil); IR (neat): ν_max 2957, 2927, 2855, 2149, 1449 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.01–7.97 (m, 2H), 7.52–7.42 (m, 3H), 2.71 (t, J = 7.5 Hz, 2H), 1.82–1.71 (m, 2H), 1.46–1.31 (m, 4H), 0.94–0.91 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 162.8, 162.5, 130.3, 128.8, 126.6, 126.2, 105.3, 31.3, 26.6, 24.6, 22.3, 13.9; HRMS (ESI) calcd for C₁₄H₁₇ClNO (M + H)⁺ (Cl-35) 250.0993, found 250.1005.

4-Bromo-3-pentyl-5-phenylisoxazole (2o-Br). Yield 47.9 mg (81%, colorless oil); IR (neat): ν_max 3065, 2930, 2860, 1445, 1410, 1060, 689 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.05–8.01 (m, 2H), 7.53–7.48 (m, 3H), 2.71 (t, J = 7.5 Hz, 2H), 1.82–1.72 (m, 2H), 1.46–1.33 (m, 4H), 0.95–0.90 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 164.2, 163.8, 130.4, 128.8, 126.9, 126.7, 90.6, 31.4, 26.8, 25.4, 22.3, 13.9; HRMS (ESI) calcd for C₁₄H₁₇BrNO (M + H)⁺ (Br-79) 294.0488, found 294.0499.

4-Chloro-5-phenyl-3-undecylisoxazole (2p). Yield 48.6 mg (58%, colorless oil); IR (neat): ν_max 2924, 2854, 1594, 1449, 1072, 766, 689 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.01–7.97 (m, 2H), 7.52–7.45 (m, 3H), 2.71 (t, J = 7.5 Hz, 2H), 1.81–1.71 (m, 2H), 1.44–1.26 (m, 16H), 0.88 (t, J = 6.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 162.8, 162.5, 130.3, 128.8, 126.6, 126.3, 105.3, 31.9, 29.6, 29.5, 29.3, 29.21, 29.20, 27.0, 24.6, 22.7, 14.1; HRMS (ESI) calcd for C₂₀H₂₉ClNO (M + H)⁺ (Cl-35) 334.1932, found 334.1938.

4-Chloro-3-isopropyl-5-phenylisoxazole (2q-Cl). Yield 62.1 mg (76%, colorless oil); IR (neat): ν_max 3063, 2973, 2934, 1448, 1131, 768, 690 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.99 (dd, J = 7.8, 2.1 Hz, 2H), 7.53–7.44 (m, 3H), 3.13 (sept, J = 7.2 Hz, 1H), 1.40 (d, J = 6.9 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 166.9, 162.8, 130.3, 128.8, 126.6, 126.4, 104.7, 26.0, 20.2; HRMS (ESI) calcd for C₁₂H₁₃ClNO (M + H)⁺ (Cl-35) 222.0680, found 222.0685.

4-Bromo-3-isopropyl-5-phenylisoxazole (2q-Br). Yield 78.4 mg (89%, colorless oil); IR (neat): ν_max 3062, 2972, 2931, 2878, 1948, 1447, 1036, 767 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.04–8.00 (m, 2H), 7.52–7.48 (m, 3H), 3.11 (sept, J = 6.9 Hz, 1H), 1.41 (d, J = 6.9 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 167.8, 164.4, 130.4, 128.7, 126.9, 126.8, 89.9, 26.6, 20.4; HRMS (ESI) calcd for C₁₂H₁₃BrNO (M + H)⁺ (Br-79) 266.0175, found 266.0179.

3-(sec-Butyl)-4-chloro-5-phenylisoxazole (2r). Yield 42.7 mg (72%, colorless oil); IR (neat): ν_max 3526, 2968, 2934, 2877, 2152, 1449, 1131, 768, 689 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.00 (dd, J = 7.8, 2.1 Hz, 2H), 7.53–7.44 (m, 3H), 2.95 (sex, J = 7.2 Hz, 1H), 1.91 (sept, J = 7.5 Hz, 1H), 1.71 (sept, J = 7.2 Hz, 1H), 1.38 (d, J = 7.2 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.0, 162.7, 130.3, 128.8, 126.7, 126.3, 104.9, 32.6, 27.5, 17.9, 11.7; HRMS (ESI) calcd for C₁₃H₁₅ClNO (M + H)⁺ (Cl-35) 236.0837, found 236.0845.

4-Chloro-3-cyclohexyl-5-phenylisoxazole (2s-Cl)¹⁴. Yield 50.6 mg (77%, white solid); mp 63.9–64.5 °C; IR (neat): ν_max 3065, 2930, 2854, 1960, 1448, 1129, 768, 689 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.98 (dd, J = 7.8, 1.8 Hz, 2H), 7.51–7.42 (m, 3H), 2.80 (tt, J = 11.7, 3.3 Hz, 1H), 2.06–2.02 (m, 2H), 1.90–1.85 (m, 2H), 1.78–1.58 (m, 3H), 1.48–1.25 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.0, 162.5, 130.2, 128.7, 126.6, 126.3, 104.7, 35.3, 30.4, 26.1, 25.8; HRMS (ESI) calcd for C₁₅H₁₇ClNO (M + H)⁺ (Cl-35) 262.0993, found 262.0991.

4-Bromo-3-cyclohexyl-5-phenylisoxazole (2s-Br). Yield 91.1 mg (78%, yellow oil); IR (neat): ν_max 3064, 2929, 2853, 1447, 1414, 1070, 768 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 8.03–7.99 (m, 2H), 7.51–7.46 (m, 3H), 2.77 (tt, J = 11.7, 3.6 Hz, 1H), 2.07–2.03 (m, 2H), 1.90–1.85 (m, 2H), 1.78–1.57 (m, 3H), 1.48–1.25 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 167.0, 164.1, 130.3, 128.7, 126.8, 126.7, 89.9, 35.9, 30.6, 26.1, 25.8; HRMS (ESI) calcd for C₁₅H₁₇BrNO (M + H)⁺ (Br-79) 306.0488, found 306.0498.

3-(tert-Butyl)-4-chloro-5-phenylisoxazole (2t). Yield 138.6 mg (88%, colorless oil); IR (neat): ν_max 3063, 2973, 2935, 2873, 1574, 1050, 768, 689 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.99–7.96 (m, 2H), 7.52–7.43 (m, 3H), 1.48 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 167.8, 163.7, 130.3, 128.7, 126.7, 126.5, 104.4, 33.2, 27.7; HRMS (ESI) calcd for C₁₃H₁₅ClNO (M + H)⁺ (Cl-35) 236.0837, found 236.0841.

5-Butyl-4-chloro-3-pentylisoxazole (2u-Cl). Yield 43.4 mg (47%, colorless oil); IR (neat): ν_max 2958, 2932, 2863, 2152, 1610, 1122, 1053, 891 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.74 (t, J = 7.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H), 1.73–1.66 (m, 4H), 1.43–1.30 (m, 6H), 0.96–0.88 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 168.0, 161.4, 105.9, 31.4, 28.8, 26.6, 24.9, 24.6, 22.3, 22.1, 13.9, 13.6; HRMS (ESI) calcd for C₁₂H₂₁ClNO (M + H)⁺ (Cl-35) 230.1306, found 230.1297.

4-Bromo-5-butyl-3-pentylisoxazole (2u-Br). Yield 49.3 mg (60%, colorless oil); IR (neat): ν_max 2958, 2932, 2863, 1602, 1466, 1416, 1057, 890 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.74 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 1.75–1.63 (m, 4H), 1.43–1.31 (m, 6H), 0.96–0.88 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 169.9, 162.4, 91.5, 31.4, 28.9, 26.7, 25.5, 25.3, 22.3, 22.1, 13.9, 13.6; HRMS (ESI) calcd for C₁₂H₂₁BrNO (M + H)⁺ (Br-79) 274.0801, found 274.0808.

5-Butyl-4-iodo-3-pentylisoxazole (2u-I). Yield 49.3 mg (55%, yellow oil); IR (neat): ν_max 2957, 2931, 2862, 1587, 1465, 1047, 894, 763 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 2.77 (t, J = 7.5 Hz, 2H), 2.59 (t, J = 7.5 Hz, 2H), 1.75–1.63 (m, 4H), 1.43–1.31 (m, 6H), 0.96–0.89 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 173.3, 164.3, 58.9, 31.3, 29.2, 27.0, 26.6, 26.5, 22.3, 22.1, 13.9, 13.6; HRMS (ESI) calcd for C₁₂H₂₁INO (M + H)⁺ (I-131) 322.0662, found 322.0655.

Acknowledgements

This research work was supported in part by grants from the Chulabhorn Research Institute, Mahidol University, and the Center of Excellence on Environmental Health and Toxicology, Science & Technology Postgraduate Education and Research Development Office (PERDO), Ministry of Education.

Notes and references

1. (a) A. M. S. Silva, A. C. Tome, T. M. V. Pinhoe Melo and J. Elguero, in Modern Heterocyclic Chemistry, ed. J. Alvarez-Builla, J. J. Vaquero and J. Barluenga, Wiley-VCH, Weinheim, Germany, 2011, pp. 727–808; (b) P. Grînanger and P. Vita-Finzi, in Chemistry of Heterocyclic Compounds, ed. E. C. Taylor, John Wiley & Sons, New York, 1991, vol. 49, part 1, pp. 1–116; (c) P. Grînanger and P. Vita-Finzi, in Chemistry of Heterocyclic Compounds, ed. E. C. Taylor and P. Wipf, John Wiley & Sons, New York, 1999, vol. 49, part 2, pp. 1–888; (d) T. Eicher, S. Hauptmann and A. Speicher, in The Chemistry of Heterocycles, Structures, Reactions, Synthesis, and Applications, Wiley-VCH, Weinheim, Germany, 2012, pp. 185–193; (e) T. M. V. D. Pinho e Melo, Curr. Org. Chem., 2005, 9, 925; (f) F. Hua and M. Szostak, Adv. Synth. Catal., 2015, 357, 2583.
2. (a) M. Z. Hernandes, S. M. T. Cavalcanti, D. R. M. Moreira, W. Filgueira de Azevedo Jr and A. C. L. Leite, Curr. Drug Targets, 2010, 11, 303; (b) P. Aroonkit, C. Thongsornkleeb, J. Tummatorn, S. Krajangsri, M. Mungthin and S. Ruchirawat, Eur. J. Med. Chem., 2015, 94, 56.
3. (a) Handbook of Organopalladium Chemistry for Organic Synthesis, ed. E. Negishi and A. de Meijere, John Wiley & Sons, Inc., New York, 2002, vol. 1 and 2; (b) Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere and F. Diederich, Wiley-VCH, Weinheim, Germany, 2004; (c) Metal-Catalyzed Cross-Coupling Reactions and More, ed. A. de Meijere, S. Bräse and M. Oestreich, Wiley-VCH, Weinheim, Germany, 2014; (d) New Trend in Cross-Coupling: Theory and Applications, ed. T. J. Colacot, RSC Catalysis Series 21, Royal Society of Chemistry, Cambridge, UK, 2015.
4. (a) Y. Jeong, B.-I. Kim, J. K. Lee and J.-S. Ryu, J. Org. Chem., 2014, 79, 6444; (b) D.-H. Song and J.-S. Ryu, Bull. Korean Chem. Soc., 2014, 35, 2635.
5. (a) J. P. Waldo and R. C. Larock, Org. Lett., 2005, 7, 5203; (b) J. P. Waldo and R. C. Larock, J. Org. Chem., 2007, 72, 9643.
6. (a) R. A. Day, J. A. Blake and C. E. Stephens, Synthesis, 2003, 1586; (b) S. D. Sokolov and I. M. Yudintseva, Chem. Heterocycl. Compd., 1973, 9, 1199; (c) R. Palin, L. Abernethy, N. Ansari, K. Cameron, T. Clarkson, M. Dempster, D. Dunn, A.-M. Easson, D. Edwards, J. Maclean, K. Everett, H. Feilden, K.-K. Ho, S. Kultgen, P. Littlewood, D. McArthur, D. McGregor, H. McLuskey, I. Neagu, S. Neale, L.-A. Nisbet, M. Ohlmeyer, Q. Pham, P. Ratcliffe, Y. Rong, A. Roughton, M. Sammons, R. Swanson, H. Tracey and G. Walker, Bioorg. Med. Chem. Lett., 2011, 21, 892; (d) S. Lopes, C. M. Nunes, R. Fausto and T. M. V. D. Pinho e Melo, J. Mol. Struct., 2009, 919, 47; (e) E. J. Bjerrum, A. S. Kristensen, D. S. Pickering, J. R. Greenwood, B. Nielsen, T. Liljefors, A. Schousboe, H. Bräuner-Osborne and U. Madsen, J. Med. Chem., 2003, 46, 2246; (f) S. Keiko, Y. Takahiro, T. Akihiro, N. Tomohiro and Y. Mitsuhiro, Nitrogen-Containing Aromatic Heterocyclyl Compound, European Patent EP2308838 (A1), April 13, 2011.
7. T. Maibunkaew, C. Thongsornkleeb, J. Tummatorn, A. Bunrit and S. Ruchirawat, Synlett, 2014, 25, 1769.
8. (a) C.-F. Lin, W.-D. Lu, I.-W. Wang and M.-J. Wu, Synlett, 2003, 13, 2057; (b) J. Zhou, G.-L. Zhang, J.-P. Zou and W. Zhang, Eur. J. Org. Chem., 2011, 2011, 3412; (c) J. Yuan, J. Wang, G. Zhang, C. Liu, X. Qi, Y. Lan, J. T. Miller, A. J. Kropf, E. E. Bunel and A. Lei, Chem. Commun., 2014, 51, 576; (d) R. Harigae, K. Moriyama and H. Togo, J. Org. Chem., 2014, 79, 2049.
9. (a) Y. Tohda, K. Sonogashira and N. Hagihara, Synthesis, 1977, 777; (b) L. Chen and C.-J. Li, Org. Lett., 2004, 6, 3151; (c) R. J. Cox, D. J. Ritson, T. A. Dane, J. Berge, J. P. H. Charmant and A. Kantacha, Chem. Commun., 2005, 1037; (d) E. Mohammadi, B. Movassagh and M. Navidi, Helv. Chim. Acta, 2014, 97, 70.
10. (a) P. Beak, A. Basha, B. Kokko and D. Loo, J. Am. Chem. Soc., 1986, 108, 6016; (b) I. R. Baxendale, S. C. Schou, J. Sedelmeier and S. V. Ley, Chem. –Eur. J., 2010, 16, 89; (c) Z. She, D. Niu, L. Chen, M. A. Gunawan, X. Shanja, W. H. Hersh and Y. Chen, J. Org. Chem., 2012, 77, 3627; (d) A. Sperança, B. Godoi and G. Zeni, J. Org. Chem., 2013, 78, 1630.
11. Pure (E)-1m was separated from the isomeric mixture via SiO₂ column chromatography.
12. D. D. Dolliver, B. T. Bhattarai, A. Pandey, M. L. Lanier, A. S. Bordelon, S. Adhikari, J. A. Dinser, P. F. Flowers, V. S. Wills and C. L. Schneider, J. Org. Chem., 2013, 78, 3676.
13. T. Tsuritani, K. Yagi, H. Shinokubo and K. Oshima, Angew. Chem., Int. Ed., 2003, 42, 5613.
14. J. Barluenga, M. Tomas, L. A. Lopez, J. Jardon and V. J. Gotor, Chem. Res., 1987, 1763.
15. H. J. Barbosa, E. A. Collins, C. Hamdouchi, E. J. Hembre, P. A. Hipskind, R. D. Johnston, J. Lu, M. J. Rupp, T. Takakuwa and R. C. Thompson, US Pat., US20080113978, 2008.

---

Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra of compounds 1a–1u, 2a–2u and 3d. See DOI: 10.1039/c6ra09396e

---