TEMPO-catalyzed synthesis of 5-substituted isoxazoles from propargylic ketones and TMSN₃

Abstract

A novel and efficient TEMPO-catalyzed synthesis of 5-substituted isoxazoles from propargylic ketones and TMSN₃ via a radical mechanism process is described. This methodology provides an easy access to a variety of useful 5-substituted isoxazoles from simple and readily available propargylic ketones and TMSN₃ in good to excellent yields. A plausible reaction mechanism for this process is proposed.

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Introduction

The isoxazole core, one of the important five-membered nitrogen heterocycles, occupies an important place in organic chemistry¹ because of its wide applications in medicinal chemistry,² materials science,³ biologically active molecules,⁴ and as an intermediate in organic synthesis.⁵ For this reason, considerable research efforts have been focused on the development of novel and efficient methods for the synthesis of isoxazoles. There are three main methodologies: the cyclization of ketoxime dianions or propargylic oximes (Scheme 1A),⁶ [3 + 2] cycloaddition reactions (Scheme 1B),⁷ and condensations with hydroxylamine (Scheme 1C).⁸ For example, in 2005, Larock and co-workers reported the isoxazole products obtained from cycloisomerizations of propargylic oximes with ICl, I₂, Br₂, or PhSeBr.^6a The Fokin group in 2008 reported a Ru(II)-catalyzed [3 + 2] cycloaddition of alkynes with nitrile oxides to give 3,4-disubstituted isoxazoles.^7b And in 2014, Liang reported the synthesis of disubstituted isoxazoles from homopropargylic alcohol, t-BuONO, and H₂O via condensation with hydroxylamine.^8c Very recently, Reddy et al. reported the direct tandem azidation and denitrogenative cyclization of internal propargylic ketones with trimethylsilyl azide as an amino surrogate (Scheme 1D).⁹ However, they did not elaborate their methodology with unsubstituted propargylic ketones. Although, the poly-substituted isoxazoles could be get by these methods which are general, regioselective, and high yielding, only a limited number of methods for the synthesis of 5-substituted isoxazoles have been described.¹⁰ Furthermore, some of these methods face the limitation of low atom efficiency, substrate specificity or forcing conditions. Therefore, the development of new methods for the regioselective synthesis of 5-substituted isoxazoles under mild reaction conditions is still highly desired.

Scheme 1 Synthesis of isoxazoles.

Recently, organocatalysis has attracted considerable attention and has been significantly developed.¹¹ 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO), a shelf-stable radical species, is the catalyst of choice in industry and has been widely used for the oxidation of alcohols to carbonyls.¹² Notably, TEMPO has been reported as a nonmetal catalyst in C=C double-bond cleavage to produce oxo nitriles.¹³ Herein, we report a TEMPO catalyzed unsubstituted propargylic ketones to produce 5-substituted isoxazoles using a useful reagent TMSN₃ as the nitrogen source (Scheme 1).

Results and discussion

At the outset of our studies, the reaction of propargylic ketone 1a with TMSN₃ was attempted under different conditions (Table 1). When the reaction was catalyzed by TEMPO, no desired product was detected with most of propargylic ketone 1a remained (Table 1, entry 1). Then, we were glad to find that propargylic ketone 1a was converted into isoxazole 2a when Mn(OAc)₂·2H₂O (15 mol%) was employed (Table 1, entry 2). We conjectured that the reaction were carried out in the presence of H₂O. Therefore, various catalyst were subsequently screened in this reaction, such as CuBr, MnO₂, MnCl₂, MnBr₂ and TEMPO (Table 1, entries 3–7). Among them, TEMPO was found to be the optimal one and afforded product 2a in 76% yield (Table 1, entry 7). Subsequently, various solvents examined, DMSO, toluene, CH₂Cl₂, 1,4-dioxane and DMF turned out to give the product (Table 1, entries 8–12). To our delight, in CH₃OH without H₂O, TEMPO performed well with high effectivity delivering the product in good yield (78% isolated yield, Table 1, entry 13). CH₂Cl₂ and 1,4-dioxane without H₂O were tested, we can not get the desired product (Table 1, entries 14–15).

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.3 mmol), TMSN3 (0.45 mmol), catalyst (15 mol%) in solvent (2 mL) at room temperature for 12 h under air. PPh3 (1.0 equiv.) was added after 12 h and the mixture was stirred for another 1 h.b Isolated yield of pure product based on 1a.c 0.2 mL H2O was added.
1	TEMPO	CH3CN	N.R.
2	Mn(OAc)2·2H2O	CH3CN	55%
3^c	CuBr	CH3CN/H2O	N.R.
4^c	MnO2	CH3CN/H2O	N.R.
5^c	MnCl2	CH3CN/H2O	N.R.
6^c	MnBr2	CH3CN/H2O	63%
7^c	TEMPO	CH3CN/H2O	76%
8^c	TEMPO	DMSO/H2O	40%
9^c	TEMPO	Toluene/H2O	47%
10^c	TEMPO	CH2Cl2/H2O	71%
11^c	TEMPO	1,4-Dioxane/H2O	74%
12	TEMPO	DMF/H2O	69%
13	TEMPO	CH3OH	78%
14	TEMPO	CH2Cl2	N.R.
15	TEMPO	1,4-Dioxane	N.R.

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With the optimized conditions in hand, the scope of substrates that could participate in the reaction was next investigated (Table 2). The acetylenic ketones 1a–1s were either commercially available or prepared using a known procedure (see ESI†). To our delight, aryl–alkynyl ketones bearing various substitutes participated well in the cyclization reaction, gave 5-substituted isoxazoles 2a–2j in moderate to good yields (70–85%). And the substrate with an electron-withdrawing group on the aromatic ring gave better yield than that of an electron-donating group on the aromatic ring. The crystallization of compound 2g from ethanol gave a single crystal suitable for X-ray analysis. Fig. 1 illustrates the molecular structure of the 5-substituted isoxazole 2g. When the aryl group was substituted in the 2-, 3-, and 4-positions by a CH₃ group, the corresponding isoxazole compound could be synthesized in 76%, 78%, and 77% yield, respectively. Gratifyingly, 5-(2-bromo-5-methoxyphenyl)isoxazole (1i) and 5-(4-(tert-butyl)phenyl)isoxazole (1j) were found to the reaction, providing the desired products 2i and 2j in 79% and 70% yield, respectively. Fortunately, propargylic ketones containing heteroaryl units or condensed rings were also tolerated (2k, 2l and 2m). It should be noted that the reactions with the alkyl acetylenic ketone, leading to moderate yields of products (2n, 2o). Similarly, propargylic ketones having a vinylic substituent (1p) and an acetylenic substituent (1q) gave the corresponding isoxazoles 2p and 2q in 67% and 66% yield, respectively. In addition, 4-phenylpent-1-yn-3-one (1r) was not an appropriate starting material under these reaction conditions. When the optically active acetylenic ketone (R)-1-(2,2′-diisopropoxy-[1,1′-binaphthalen]-3-yl)prop-2-yn-1-one was examined as a substrate, to our delight, (R)-5-(2,2′-diisopropoxy-[1,1′-binaphthalen]-3-yl)isoxazole 2s was formed in 55% yield.

Table 2 Substrate scope for the reaction of propargylic ketones 1 and TMSN₃^a,b

a Reaction conditions: 1 (0.3 mmol), TMSN₃ (0.45 mmol), TEMPO (15 mol%) in CH₃OH (2 mL) under air at room temperature. PPh₃ (1.0 equiv.) was added after 12 h and the mixture was stirred for another 1 h.b Isolated yield of pure product based on 1.

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Fig. 1 X-ray crystal structure of 5-substituted isoxazole 2g (CCDC: 1449503†).

To our disappointment, internal propargylic ketones could not provide the desired product using the current catalytic system. Internal propargylic ketone 3 was tested under the standard conditions, providing the 4,5-disubstituted 1,2,3-triazole 4 in 82% yield (eqn (1)).

Some control experiments were carried out in order to explore the possible reaction pathway. CH₃¹⁸OH and ¹⁸O₂ isotopic labeling experiments were investigated. As expected, the oxygen atom of 2a originated from propargylic ketone 1a (eqn (2) and (3), the results were determined by HRMS, see ESI†). Furthermore, CH₃OD was investigated to the reaction and produced the deuterated product 2a–d in 78% yield (eqn (4)). And the deuterated substrate 1a–d′ was subjected to the reaction and produced the product 5-phenylisoxazole 2a–d′ in 77% yield (eqn (5)).

On the basis of the preliminary results, a plausible pathway is proposed for this cascade reaction (Scheme 2). Initially, TMSN₃ generates azido free radical associated with the formation of intermediate A. The TEMPO–TMS species A reacts with CH₃OH to form TEMPOH B and CH₃O–TMS. The azido free radical subsequently attacks the alkyne to form radical intermediate 5. Subsequently, the radical 5 reacts directly with the TEMPOH species B, yields the intermediate 6 which is detected by HRMS (see ESI†), with the regeneration of the catalyst. The intramolecular azide–alkene cycloaddition was performed to afford triazole species 7. This triazole 7 undergoes homolytic cleavage to give radical intermediate 8, which release N₂ to give the imine 9. Then, one-electron shift, followed by a subsequently intramolecular radical coupling to afford the product 2a. The intermolecular [3 + 2] cycloaddition reaction of internal propargylic ketone with TMSN₃ were occurred during the standard conditions because of the effect of steric hindrance.

Scheme 2 A plausible reaction mechanism.

Conclusions

In summary, we have demonstrated a facile transformation of propargylic ketones into 5-substituted isoxazoles catalyzed by TEMPO. The reaction has been delineated to proceed by a radical mechanism. Readily available, cheap starting substrates, an inexpensive catalyst, metal-free mild reaction conditions, a simple experimental procedure, and good yields, are some of the attractive attributes of the present protocol. Further work concerning synthetic applications and biological assessment of these isoxazoles is underway and the results shall be reported in due course.

Experimental

General remarks

Melting points were measured with a SGW X-4 melting point instrument (uncorrected). Proton nuclear magnetic resonance spectra (¹H NMR) and carbon nuclear magnetic resonance spectra (¹³C NMR) were recorded at 400 MHz and 100 MHz, respectively, using CDCl₃ as reference standard (δ 7.26 ppm) for ¹H NMR and (δ 77 ppm) for ¹³C NMR. HRMS (ion trap) were recorded using ESI. Precoated silica gel plates GF-254 were used for thin-layer analytical chromatography. Column chromatography was performed on silica gel (300–400 mesh). Starting materials azidomethyl aromatics were readily prepared according to literature procedures. Unless otherwise noted, all reagents were obtained commercially and used without further purification.

General procedure for the synthesis of 5-substituted isoxazoles

To the mixture of propargylic ketones (1.0 equiv., 0.3 mmol) and azides (1.5 equiv., 0.45 mmol), TEMPO (15 mol%), and 2.0 mL CH₃OH at 25 °C for 12 h in the air. PPh₃ (1.0 equiv.) was added after 12 h and the mixture was stirred for another 1 h. The progress of the reaction was monitored by thin-layer chromatography. Upon completion, the mixture was evaporated under reduced pressure, and the residue was separated by column chromatography (ethyl acetate/petroleum ether = 1 : 40 to 1 : 20) to give the pure product.

5-Phenylisoxazole (2a). Colorless solid; mp 79–81 °C (lit.¹⁴ 80–81 °C); ¹H NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.78 (d, J = 7.1 Hz, 2H), 7.48–7.39 (m, 3H), 6.50 (s, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.24, 150.73, 130.07, 128.88, 127.15, 125.73, 98.57 ppm; HRMS (m/z) (ESI): calcd for C₉H₇NO 146.06059 [M + H⁺]; found 146.05994.

5-(o-Tolyl)isoxazole (2b). White oil; ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J = 1.8 Hz, 1H), 7.72 (dd, J = 5.6, 3.5 Hz, 1H), 7.38–7.33 (m, 1H), 7.33–7.28 (m, 2H), 6.43 (d, J = 1.8 Hz, 1H), 2.51 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.39, 150.44, 136.16, 131.30, 129.97, 128.51, 126.84, 126.19, 101.73, 21.39 ppm; HRMS (m/z) (APCI): calcd for C₁₀H₉NO 160.07624 [M + H⁺]; found 160.07557.

5-(m-Tolyl)isoxazole (2c). Light yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.59 (d, J = 11.3 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 6.49 (s, 1H), 2.40 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.45, 150.69, 138.66, 130.88, 128.79, 127.08, 126.34, 122.92, 98.46, 21.26 ppm; HRMS (m/z) (APCI): calcd for C₁₀H₉NO 160.07624 [M + H⁺]; found 160.07556.

5-(p-Tolyl)isoxazole (2d). Colorless solid; mp 55–57 °C (lit.¹⁵ 60–61 °C); ¹H NMR (500 MHz, CDCl₃) δ 8.29 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 6.49 (d, J = 1.8 Hz, 1H), 2.42 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.53, 150.74, 140.44, 129.64, 125.78, 124.58, 98.00, 21.41 ppm; HRMS (m/z) (APCI): calcd for C₁₀H₉NO 160.07624 [M + H⁺]; found 160.07550.

5-(4-Fluorophenyl)isoxazole (2e). Colorless solid; mp 46–52 °C (lit.¹⁶ 51–53 °C); ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J = 1.8 Hz, 1H), 7.81–7.74 (m, 2H), 7.19–7.12 (m, 2H), 6.47 (d, J = 1.8 Hz, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 168.43, 165.00, 162.51, 150.89, 127.99, 127.91, 123.69, 123.66, 116.34, 116.12, 98.46 ppm; HRMS (m/z) (APCI): calcd for C₉H₆FNO 164.05117 [M + H⁺]; found 164.05047.

5-(4-Chlorophenyl)isoxazole (2f). Colorless solid; mp 79–83 °C (lit.¹⁶ 84–85 °C); ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.50 (s, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 168.20, 150.84, 136.20, 129.27, 127.07, 125.68, 98.94 ppm; HRMS (m/z) (APCI): calcd for C₉H₆ClNO 180.02162 [M + H⁺]; found 180.02066.

5-(4-Bromophenyl)isoxazole (2g). Colorless solid; mp 114–115 °C (lit.¹⁶ 114–116 °C); ¹H NMR (500 MHz, CDCl₃) δ 8.28 (d, J = 1.9 Hz, 1H), 7.66–7.63 (m, 2H), 7.60–7.57 (m, 2H), 6.51 (d, J = 1.9 Hz, 1H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 168.26, 150.81, 132.24, 127.28, 126.14, 124.51, 99.00 ppm; HRMS (m/z) (APCI): calcd for C₉H₆BrNO 223.97110 [M + H⁺]; found 223.97028.

5-(3-(Trifluoromethyl)phenyl)isoxazole (2h). White oil; ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J = 1.7 Hz, 1H), 8.03 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 6.61 (d, J = 1.7 Hz, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 167.72, 150.91, 132.10, 131.77, 131.44, 131.12, 129.65, 128.92, 128.91, 127.94, 126.72, 126.68, 126.65, 126.61, 124.97, 122.73, 122.69, 122.65, 122.61, 122.27, 99.68 ppm; HRMS (m/z) (APCI): calcd for C₁₀H₆F₃NO 214.04797 [M + H⁺]; found 214.04721.

5-(2-Bromo-5-methoxyphenyl)isoxazole (2i). Colorless solid; mp 62–65 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 6.99 (d, J = 1.9 Hz, 1H), 6.84 (dd, J = 8.9, 3.1 Hz, 1H), 3.83 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 166.80, 158.88, 150.49, 134.85, 128.58, 117.71, 114.66, 111.38, 103.41, 55.58 ppm; HRMS (m/z) (APCI): calcd for C₁₀H₈BrNO₂ 253.98167 [M + H⁺]; found 253.98083.

5-(4-(tert-Butyl)phenyl)isoxazole (2j). White oil; ¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 6.47 (s, 1H), 1.35 (s, 9H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.43, 153.53, 150.70, 125.86, 125.60, 124.49, 98.07, 34.80, 31.07 ppm; HRMS (m/z) (APCI): calcd for C₁₃H₁₅NO 202.12319 [M + H⁺]; found 202.12237.

5-(Naphthalen-2-yl)isoxazole (2k). Colorless solid; mp 92–94 °C (lit.¹⁷ 93–95 °C); ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J = 10.5 Hz, 2H), 7.92–7.88 (m, 2H), 7.86–7.80 (m, 2H), 7.56–7.52 (m, 2H), 6.61 (s, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 169.35, 150.96, 133.80, 132.96, 128.77, 128.56, 127.74, 127.23, 126.83, 125.51, 124.39, 122.83, 98.99 ppm; HRMS (m/z) (APCI): calcd for C₁₃H₉NO 196.07624 [M + H⁺]; found 196.07550.

5-(Furan-2-yl)isoxazole (2l). Light yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 1.4 Hz, 1H), 6.92 (d, J = 3.4 Hz, 1H), 6.54 (dd, J = 3.3, 1.7 Hz, 1H), 6.45 (d, J = 1.6 Hz, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 161.05, 150.39, 144.05, 143.21, 111.91, 110.45, 98.25 ppm; HRMS (m/z) (APCI): calcd for C₇H₅NO₂ 136.03985 [M + H⁺]; found 136.03930.

5-(Thiophen-2-yl)isoxazole (2m). Yellow oil; ¹H NMR (500 MHz, CDCl₃) δ 8.25 (d, J = 1.8 Hz, 1H), 7.51 (dd, J = 3.7, 1.1 Hz, 1H), 7.44 (dd, J = 5.0, 1.1 Hz, 1H), 7.12 (dd, J = 5.0, 3.7 Hz, 1H), 6.38 (d, J = 1.8 Hz, 1H) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 164.25, 150.59, 128.98, 127.93, 127.87, 126.91, 98.28 ppm; HRMS (m/z) (ESI): calcd for C₇H₅NOS 152.01701 [M + H⁺]; found 152.01649.

5-Benzylisoxazole (2n). Yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.31 (t, J = 7.1 Hz, 2H), 7.23 (d, J = 7.3 Hz, 3H), 5.89 (s, 1H), 4.08 (s, 2H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 171.46, 150.34, 135.88, 128.77, 127.12, 101.03, 33.01 ppm; HRMS (m/z) (APCI): calcd for C₁₀H₉NO 160.07624 [M + H⁺]; found 160.07562.

5-Phenethylisoxazole (2o). Yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.30 (t, J = 7.3 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.18 (d, J = 7.1 Hz, 2H), 5.93 (s, 1H), 3.11 (dd, J = 11.6, 4.7 Hz, 2H), 3.02 (dd, J = 11.5, 4.8 Hz, 2H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 171.71, 150.20, 139.95, 128.51, 128.24, 126.41, 100.37, 33.56, 28.29 ppm; HRMS (m/z) (APCI): calcd for C₁₁H₁₁NO 174.09189 [M + H⁺]; found 174.09128.

(E)-5-Styrylisoxazole (2p). Colorless solid; mp 41–43 °C (lit.¹⁸ 42–43 °C); ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J = 1.7 Hz, 1H), 7.48–7.43 (m, 2H), 7.36–7.24 (m, 4H), 6.93 (d, J = 16.4 Hz, 1H), 6.20 (d, J = 1.7 Hz, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 167.86, 150.62, 135.49, 134.95, 129.17, 128.87, 127.10, 112.85, 100.67 ppm; HRMS (m/z) (APCI): calcd for C₁₁H₉NO 172.07624 [M + H⁺]; found 172.07556.

5-(Phenylethynyl)isoxazole (2q). Yellow oil; ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J = 1.7 Hz, 1H), 7.58 (dd, J = 7.9, 1.6 Hz, 2H), 7.44–7.37 (m, 3H), 6.50 (d, J = 1.7 Hz, 1H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 153.08, 150.34, 131.86, 129.89, 128.56, 120.82, 107.02, 98.65, 75.29 ppm; HRMS (m/z) (APCI): calcd for C₁₁H₇NO 170.06059 [M + H⁺]; found 170.05984.

5-(1-Phenylethyl)isoxazole (2r). Yellow oil; HRMS (m/z) (ESI): calcd for C₁₁H₁₁NO 173.08406 [M − H⁺]; found 172.07597.

(R)-5-(2,2′-Diisopropoxy-[1,1′-binaphthalen]-3-yl)isoxazole (2s). Light yellow oil; [α]²⁰_D = +62 (c 0.22, CH₃OH); ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.34 (t, J = 3.8 Hz, 1H), 7.96 (dd, J = 8.4, 5.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.34–7.30 (m, 1H), 7.24 (dd, J = 12.9, 6.3 Hz, 3H), 7.18 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 1.2 Hz, 1H), 4.55 (dt, J = 11.9, 5.9 Hz, 1H), 3.87–3.78 (m, 1H), 1.15 (d, J = 5.9 Hz, 3H), 1.02 (d, J = 6.0 Hz, 3H), 0.81 (d, J = 6.1 Hz, 3H), 0.69 (d, J = 6.2 Hz, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 166.17, 152.78, 150.33, 150.09, 133.91, 133.07, 129.16, 129.02, 128.07, 127.92, 127.36, 127.11, 126.27, 125.85, 125.61, 124.95, 124.44, 124.30, 122.77, 121.40, 119.13, 114.60, 102.89, 75.13, 69.92, 21.55, 21.50, 21.39 ppm; HRMS (m/z) (ESI): calcd for C₂₉H₂₈NO₃ 438.20692 [M + H⁺]; found 438.20599.

Acknowledgements

We would like to thank National Natural Science Foundation of China (21362002 and 81260472), State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (CMEMR2014-A02 and CMEMR2012-A20), Guangxi's Medicine Talented Persons Small Highland Foundation (1306), and The Fund of Guangxi Key Laboratory of Functional Phytochemicals Research and Utilization (FPRU2015-2) for financial support.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: General experimental procedures, and spectral data, NMR spectra, high resolution mass spectra for all compounds, and X-ray crystallographic files (CIF) for 2g. CCDC 1449503. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra11099a

‡ These authors contributed equally to this work.

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