Novel exocyclic enamides: synthesis and evaluation of the fungicidal activities of 5-methylene-2-(trifluoromethyl)morpholin-3-one derivatives

Abstract

Exocyclic enamides have been used extensively in the synthesis of natural products and biologically active substances. A facile and efficient protocol has been developed for the synthesis of a series of new 5-methylenemorpholin-3-one derivatives, which are exocyclic enamides, based on the reactions of trifluoroatrolactamides with propargyl bromide in the presence of sodium hydride. The biological evaluation of these compounds showed that some of them exhibited very good in vitro fungicidal activity against P. oryzae. For example, compounds 2d and 2e gave fungicidal activities of 50% at a concentration of 0.9 μg mL⁻¹, whilst the control compound fenaminstrobin gave 80% activity at the same concentration.

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Introduction

Exocyclic enamides,¹ which display a fine balance of stability and reactivity, have been used extensively for the synthesis of natural products. Compounds belonging to this structural class have also been used as building blocks for the synthesis of a wide variety of interesting compounds, including cobyric acid,² prostaglandin analogs,³ γ-lactam antibiotics⁴ and angiotensin II antagonists,⁵ as well as several other biologically active molecules.^6–9

Morpholinone and its derivatives are important heterocycles, which have been reported to exhibit a wide range of biological properties, including renin inhibition,^10,11 antagonist,¹² antithrombotic and¹³ herbicidal¹⁴ activities. 5-Methylenemorpholin-3-one, which is a novel exocyclic enamide, has only ever been reported as a byproduct^15,16 or a substructure of 4-methylene-6,8-dioxa-3-azabicyclo[3.2.1]octan-2-one derivatives¹⁷ with ischemia-reperfusion-related pathologies. Furthermore, 3-methylenepiperazine-2,5-dione, which is an isostere of 5-methylenemorpholin-3-one, has been found in several natural products, such as isoechinulin B and neoechinulin B.¹⁸

We previously reported that trifluoroatrolactamides 1 were readily prepared using an efficient ultrasound-promoted method.^19,20 Herein, we report the development of a convenient method for the synthesis of the 5-methylenemorpholin-3-one derivatives 2 and 3 as novel exocyclic enamides via the cyclization of trifluoroatrolactamides 1 with propargyl bromide (Scheme 1). Compounds 2 exhibited excellent fungicidal activities and could be used as building blocks for the construction of new biologically active compounds.

Scheme 1 Synthetic route to compounds 2 and 3.

Results and discussion

Chemistry

During our recent studies towards the alkylation of trifluoroatrolactamides 1, which have been reported to exhibit high fungicidal activities, we explored a variety of different methods for the synthesis of O-propargyl compounds 1 with the aim of finding new biologically active compounds. Unfortunately, however, we did not obtain any of the desired products 4 when investigating the alkylation of compounds 1 with propargyl bromide, even when we used equimolar amounts of base and an acid binding agent. Our subsequent analysis of the material resulting from this reaction by HRMS indicated that it corresponded to the expected O-propargyl compound 1. However, the ¹H NMR of 2 did not contain a CONH signal around 7.0 ppm or a terminal alkyne hydrogen signal around 3.3 ppm. Furthermore, the ¹H NMR spectrum of this material contained a doublet of doublets around 5.0 ppm. Notably, the ¹³C NMR spectrum of 2a contained a signal around 92.8 ppm, which was inconsistent with the presence of a terminal alkyne. Two single crystals of compounds 2a and 3a were obtained using the slow evaporation solution growth technique at room temperature. The single-crystal X-ray structures of 2a and 3a showed that they contained an unexpected 5-methylenemorpholin-3-one ring structure (Fig. 1 and 2). The length of the C8–C9 double bond in compound 2a was 1.334(2) Å, which is normal for a C=C double bond. Furthermore, the C1 atom and most of the atoms in the morpholinone ring of compound 2a, excluding O2, were almost in the same plane. The two phenyl groups on the same side of the morpholinone ring projected up and away from the plane of the morpholinone ring, with the entire structure of 2a taking on the shape of the letter U. The length of the C4–C6 double bond in compound 3a was 1.3296(18) Å, which was slightly shorter than that of compound 2a. In contrast with compound 2a, compound 3a was shaped like the letter L because it did not contain a methylene bridge between its phenyl moiety and the morpholinone ring. The angle between the morpholinone and N-phenyl rings (C13–C18) in compound 3a was determined to be about 70°.

Fig. 1 Molecular structure of 2a.

Fig. 2 Molecular structure of 3a.

Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1427870 and 1427844 for 2a and 3a.†

Most of the existing approaches for the synthesis of enamide derivatives involve the use of keto amide cyclizations, where the formation of a carbinolamide intermediate is followed by a dehydration reaction. Several similar reactions have been reported for the synthesis of enamide derivatives via the direct reaction of alkyne and amides in the presence of a catalyst,^1,21–23 such as n-Bu₄NF, LiAl-(NHBn)₄, phosphine, silver(I) or homogenous zinc. However, in the current study, the addition of an N–H bond to an alkyne to give an exocyclic enamide proceeded rapidly without the need for a catalyst or excess base in good to excellent yields. The facile nature of these cyclization reactions could be attributed to the reactivity of the N-anion in intermediate 5, which would be formed by the O-propargylation of compound 1. The spontaneous formation of the N-anion in 5 would be immediately followed by the attack of the propargyl moiety in 5 to generate the exocyclic enamide 2. This reaction would occur in this way because the O-propargylation reaction would effectively facilitate the formation of a N-anion in intermediate 5 to a greater extent than the formation of an O-anion in compound 1 (Scheme 2).

Scheme 2 Possible reaction mechanism for the formation of compound 2.

Fungicidal activity

The fungicidal activities of the compounds prepared in the current study were tested against several fungi, including Pseudoperonospora cubensis, Erysiphe graminis and Puccinia sorghi Schw (in vivo) at 400 mg L⁻¹, as well as Pyricularia oryzae (in vitro) at 25 mg L⁻¹. Some of the compounds synthesized in the current study exhibited good fungicidal activities against P. oryzae. When they were dosed at 25 μg mL⁻¹, compounds bearing a N-substituted benzyl ring (n = 1), such as compounds 2a, 2d and 2e displayed a high level of fungicidal activity against P. oryzae (100% inhibition). The activities of these compounds were measured using a dose reduction method with a four-fold serial dilution. As shown in Table 2, compounds 2d and 2e displayed fungicidal activities of 80 and 50% against P. oryzae at concentrations of 2.8 and 0.9 μg mL⁻¹, respectively. The control compound, fenaminstrobin, fungicidal activities of 100 and 80% at the same concentrations, respectively. When R² was H, the order of fungicidal activities of the N-substituted benzyl compounds 2 was 2-MeO ≈ 4-MeO > H > Me > F. However, compounds where R² was not H suffered a complete lost of fungicidal against P. oryzae (e.g., 2f–i). However, it is noteworthy that compound 2i, where R² was PhO, exhibited a fungicidal activity of 100% against P. sorghi Schw at a concentration of 400 μg mL⁻¹.

Compounds with a N-substituted phenyl ring (i.e., n = 0) displayed similar trends in their fungicidal activities to those bearing a N-substituted benzyl ring (i.e., n = 1). Compounds where R² was not H suffered a completely lost in their fungicidal activity towards all four fungi. When R² was H, compounds 3c, 3d and 3g displayed fungicidal activities of 98, 80 and 80% against E. graminis at a concentration of 400 μg mL⁻¹, respectively. Furthermore, compounds 3a, 3c and 3d displayed fungicidal activities of 80, 80 and 70% against P. sorghi Schw at a concentration of 400 μg mL⁻¹, respectively. However, none of the compounds represented by structure 3 exhibited good fungicidal activity against P. oryzae.

Experimental

Material and methods

¹H, ¹³C and ¹⁹F NMR spectra were measured on a Bruker AC-P500 instrument (Bruker, Fallanden, Switzerland) using CDCl₃ as a solvent with TMS as internal reference standard. Melting points were determined on an X-4 binocular microscope melting point apparatus (Beijing Tech Instruments, Beijing, China) and were uncorrected. HRMS were recorded on an Ionspec 7.0-T Fourier-transform ion-cyclotron resonance (FTICR) mass spectrometer (Bruker, Billerica, USA). The ultrasonic irradiation experiments were conducted on a Nanjing SL2010-N ultrasonic processor (Shunliu, Nanjin, China). All of the reagents used in the current study were purchased as the analytical grade.

General procedure for the synthesis of the N-substituted-3,3,3-trifluoro-2-hydroxy-2-substituted phenylpropanamides 1

Compounds 1 were synthesized according a literature procedure using an ultrasound-promoted one-pot Passerini/hydrolysis reaction.^19,20

General procedure for the synthesis of the 4-substituted phenyl-5-methylene-2-substituted phenyl-2-(trifluoromethyl)morpholin-3-ones 2 and 4-substituted benzyl-5-methylene-2-substituted phenyl-2-(trifluoromethyl)morpholin-3-ones 3

NaH (60% dispersion in mineral oil, 0.09 g, 2.22 mmol) was added to a solution of compound 1 (1.85 mmol) and a catalytic amount of tetrabutylammoniumbromide in THF (10 mL) at room temperature, and the resulting mixture was stirred for 30 min. Alkyl bromide (80%, 0.41 g, 2.78 mmol) was then added to the reaction in a dropwise manner, and the resulting mixture was stirred at 40–50 °C for 2 h. The reaction mixture was then cooled to ambient temperature and evaporated to dryness under vacuum to give a residue, which was dissolved in EtOAc (30 mL), washed with brine and dried over MgSO₄ and filtered. The solvent was evaporated under vacuum to give a residue, which was crystallized from EtOH to give compound 2 or 3.

Data for 2a. white solid, yield = 67%, mp 79–81 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 2.4 Hz, 2H, Ar-H), 7.62–7.15 (m, 8H, Ar-H), 5.22 (d, J = 15.6 Hz, 1H, OCH₂), 4.97 (d, J = 15.6 Hz, 1H, OCH₂) 4.44 (d, 1H, J = 14 Hz, C=CH), 4.39 (d, J = 13.2 Hz, 2H, NCH₂), 4.27 (s, 1H, C=CH); ¹³C NMR (100 MHz, CDCl₃) δ 161.9, 138.5, 135.6, 130.3, 130.1, 128.9, 128.8, 127.8, 127.4, 126.5, 124.2, 121.3, 92.9, 82.1, 81.9, 63.1, 45.9; ¹⁹F NMR (376 MHz, CDCl₃) δ −75.93; HRMS (ESI) m/z calcd for C₁₉H₁₆F₃NO₂Na⁺ [M + Na]⁺ 370.1025, found 370.1023.

Data for 2b. White solid, yield = 75%, mp 104–105 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.86–7.66 (m, 2H, Ar-H), 7.60–7.35 (m, 3H, Ar-H), 7.23–7.10 (m, 2H, Ar-H), 7.01 (t, J = 8.4 Hz, 2H, Ar-H), 5.16 (d, J = 15.6 Hz, 1H, OCH₂), 4.85 (d, J = 15.6 Hz, 1H, OCH₂) 4.41 (d, J = 14 Hz, 1H, C=CH), 4.35 (d, J = 13.2 Hz, 2H, NCH₂), 4.25 (s, 1H, C=CH); ¹³C NMR (100 MHz, CDCl₃) δ 163.3, 161.9, 160.8, 138.5, 131.4, 131.3, 130.2, 130.1, 128.9, 128.3, 128.2, 127.7, 124.1, 121.2, 115.8, 115.6, 92.7, 63.0, 45.3; ¹⁹F NMR (376 MHz, CDCl₃) δ −75.77, −114.98; HRMS (ESI) m/z calcd for C₁₉H₁₅F₄NO₂Na⁺ [M + Na]⁺ 388.0931, found 388.0766.

Data for 2c. White solid, yield = 82%, mp 97–98 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.92–7.69 (m, 2H, Ar-H), 7.54–7.38 (m, 3H, Ar-H), 7.10 (q, J = 8.0 Hz, 4H, Ar-H), 5.11 (d, J = 15.6 Hz, 1H, OCH₂), 4.90 (d, J = 15.6 Hz, 1H, OCH₂), 4.39 (d, J = 13.2 Hz, 2H, NCH₂), 4.33 (d, J = 14 Hz, 1H, C=CH), 4.22 (s, 1H, C=CH), 2.31 (s, 3H, Ar-CH₃); ¹³C NMR (100 MHz, CDCl₃) δ 161.8, 138.5, 137.1, 132.6, 129.5, 128.9, 127.8, 126.6, 124.2, 121.3, 92.8, 82.1, 81.8, 77.4, 77.0, 76.7, 63.1, 45.7, 21.7; ¹⁹F NMR (376 MHz, CDCl₃) δ −75.70; HRMS (ESI) m/z calcd for C₂₀H₁₈F₃NO₂Na⁺ [M + Na]⁺ 384.1182, found 384.1185.

Data for 2d. White solid, yield = 63%, mp 87–88 °C, . ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J = 2.8 Hz, 2H, Ar-H), 7.55–7.42 (m, 3H, Ar-H), 7.23 (d, J = 8.0 Hz, 1H, Ar-H), 6.98 (d, J = 7.2 Hz, 1H, Ar-H), 6.88 (t, J = 8.0 Hz, 2H, Ar-H), 5.17 (d, J = 15.6 Hz, 1H, OCH₂), 4.94 (d, J = 15.6 Hz, 1H, OCH₂), 4.41 (d, J = 14 Hz, 1H, C=CH), 4.36 (d, J = 13.2 Hz, 2H, NCH₂), 4.19 (s, 1H, C=CH), 3.84 (s, 3H, Ar-2-OCH₃); ¹³C NMR (100 MHz, CDCl₃) δ 161.8, 156.6, 138.4, 130.5, 130.0, 128.9, 128.4, 128.3, 127.8, 126.4, 124.2, 123.4, 121.3, 120.8, 110.2, 92.7, 63.0, 55.3, 40.8; ¹⁹F NMR (376 MHz, CDCl₃) δ −75.71; HRMS (ESI) m/z calcd for C₂₀H₁₈F₃NO₃Na⁺ [M + Na]⁺ 400.1131, found 400.1132.

Data for 2e. White solid, yield = 81%, mp 90–91 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.92–7.74 (m, 2H, Ar-H), 7.59–7.41 (m, 3H, Ar-H), 7.17 (d, J = 8.0 Hz, 2H, Ar-H), 6.88 (d, J = 8.0 Hz, 2H, Ar-H), 5.13 (d, J = 15.6 Hz, 1H, OCH₂) 4.90 (d, J = 15.6 Hz, 1H, OCH₂), 4.42 (d, J = 13.2 Hz, 2H, NCH₂), 4.36 (d, J = 14 Hz, 1H, C=CH), 4.27 (s, 1H, C=CH), 3.82 (s, 3H, Ar-p-OCH₃); ¹³C NMR (100 MHz, CDCl₃) δ 161.8, 158.9, 138.5, 130.4, 130.1, 129.1, 128.9, 128.0, 127.8, 124.1, 121.3, 114.5, 114.2, 92.7, 82.1, 63.1, 55.3, 45.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −75.71; HRMS (ESI) m/z calcd for C₂₀H₁₈F₃NO₃Na⁺ [M + Na]⁺ 400.1131, found 400.1127.

Data for 2f. White solid, yield = 39.4%, mp 95–97 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J = 8.2 Hz, 2H, Ar-H), 7.23 (d, J = 6.6 Hz, 2H, Ar-H), 7.11 (d, J = 8.6 Hz, 2H, Ar-H), 6.81 (d, J = 8.6 Hz, 2H, Ar-H), 5.01 (d, J = 15.2 Hz, 1H, OCH₂) 4.79 (d, J = 15.2 Hz, 1H, OCH₂) 4.30 (d, J = 1.6 HZ, 1H, C=CH), 4.27 (s, 2H, NCH₂), 4.15 (s, 1H,C=CH), 3.75 (s, 3H, Ar-p-OCH₃), 2.66 (q, J = 7.6 Hz, 2H, Ar-p-CH₂CH₃), 1.23 (t, J = 7.6 Hz, 3H, Ar-p-CH₂CH₃); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.81; ¹³C NMR (101 MHz, CDCl₃) δ 160.9, 157.8, 145.3, 137.6, 127.4, 127.0, 126.7, 126.7, 126.4, 118.9 (q, J_F–C = 286.84 Hz), 113.1, 91.5, 61.9, 54.2, 44.2, 27.5, 14.2; HRMS (ESI) m/z calcd for C₂₂H₂₂F₃NO₃Na⁺ [M + Na]⁺ 428.1444, found 428.1447.

Data for 2g. White solid, yield = 37.5%, mp 85–87 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J = 8.8 Hz, 2H, Ar-H), 7.13 (d, J = 8.5 Hz, 2H, Ar-H), 6.96 (d, J = 8.9 Hz, 2H, Ar-H), 6.85 (d, J = 8.7 Hz, 2H, Ar-H), 5.08 (d, J = 15.2 Hz, 1H, OCH₂) 4.87 (d, J = 15.2 Hz, 1H, OCH₂) 4.38 (s, 1H, C=CH), 4.34 (d, J = 4.4 Hz, 2H, NCH₂), 4.15 (s, 1H, C=CH), 3.84 (s, 3H, Ar-p-OCH₃), 3.78 (s, 3H, Ar-p-OCH₃); ¹⁹F NMR (376 MHz, CDCl₃) δ −76.04; ¹³C NMR (101 MHz, CDCl₃) δ 162.7, 161.6, 159.6, 139.3, 129.9, 128.7, 128.5, 124.9, 122.8, 114.9, 114.9, 93.2, 63.6, 56.1, 56.0, 46.0, 43.8; HRMS (ESI) m/z calcd for C₂₁H₂₀F₃NO₄Na⁺ [M + Na]⁺ 430.1237, found 430.1242.

Data for 2h. White solid, yield = 63.0%, mp 174–175 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.1 Hz, 2H, Ar-H), 7.68 (d, J = 8.1 Hz, 2H, Ar-H), 7.61 (d, J = 7.6 Hz, 2H, Ar-H), 7.47 (t, J = 7.4 Hz, 2H, Ar-H), 7.39 (t, J = 7.2 Hz, 1H, Ar-H), 7.15 (d, J = 8.2 Hz, 2H, Ar-H), 6.86 (d, J = 8.2 Hz, 2H, Ar-H), 5.11 (d, J = 15.6 Hz, 1H, OCH₂), 4.89 (d, J = 15.6 Hz, 1H, OCH₂), 4.42 (s, 1H, C=CH), 4.40 (s, 2H, NCH₂), 4.27 (s, 1H, C=CH), 3.79 (s, 3H, Ar-p-OCH₃); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.67; ¹³C NMR (101 MHz, CDCl₃) δ 161.9, 158.9, 142.9, 140.1, 138.5, 129.3, 128.9, 128.2, 128.0, 127.9, 127.7, 127.6, 127.2, 119.9 (q, J_F–C = 285.83 Hz), 114.2, 92.8, 63.2, 62.9, 55.3, 49.6, 45.4; HRMS (ESI) m/z calcd for C₂₆H₂₂F₃NO₃Na⁺ [M + Na]⁺ 476.1444, found 476.1447.

Data for 2i. White solid, yield = 33.3%, mp 105–106 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 8.3 Hz, 2H, Ar-H), 7.38 (t, J = 7.5 Hz, 2H, Ar-H), 7.16 (dd, J = 16.6, 7.8 Hz, 3H, Ar-H), 7.10–7.02 (m, 4H, Ar-H), 6.85 (d, J = 8.0 Hz, 2H, Ar-H), 5.09 (d, J = 15.6 Hz, 1H, OCH₂), 4.86 (d, J = 15.6 Hz, 1H, OCH₂), 4.42 (s, 1H, C=CH), 4.36 (d, J = 5.2 Hz, 2H, NCH₂), 4.26 (s, 1H, C=CH), 3.79 (s, 3H, Ar-p-OCH₃); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.88; ¹³C NMR (101 MHz, CDCl₃) δ 162.6, 159.9, 159.6, 156.8, 139.2, 130.7, 130.1, 128.7, 128.4, 125.1, 124.9, 122.0, 120.5, 118.9, 114.9, 93.5, 63.7, 56.0, 46.1; HRMS (ESI) m/z calcd for C₂₆H₂₂F₃NO₄Na⁺ [M + Na]⁺ 492.1393, found 492.1395.

Data for 3a. White solid, yield = 46.8%, mp 135–136 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.79 (dd, J = 6.6, 2.9 Hz, 2H, Ar-H), 7.52–7.44 (m, 3H, Ar-H), 7.24–7.14 (m, 4H, Ar-H), 4.55 (d, J = 13.9 Hz, 1H, OCH₂), 4.48 (d, J = 13.9 Hz, 1H, OCH₂), 4.24 (s, 1H, C=CH₂), 3.86 (d, J = 1.3 Hz, 1H, C=CH₂); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.90, −112.13; ¹³C NMR (101 MHz, CDCl₃) δ 162.7, 160.8, 160.2, 140.1, 131.0, 129.3, 129.6, 129.1, 128.0, 126.7, 121.6 (q, J_F–C = 286.84 Hz), 116.0, 115.8, 92.6, 61.8; HRMS (ESI) m/z calcd for C₁₈H₁₃F₄NO₂Na⁺ [M + Na]⁺ 374.0775, found 374.0775.

Data for 3b. Yellow solid, yield = 51.7%, mp 152–154 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.85–7.75 (m, 2H, Ar-H), 7.63–7.52 (m, 1H, Ar-H), 7.51–7.30 + 7.16 (m + dd, J = 7.2, 2.1 Hz, 6H, Ar-H), 4.48 (dd, J = 24, 13.9 Hz, 1H, OCH₂), 4.51 (d, J = 13.9 Hz, 1H, OCH₂), 4.23 (s, 1H, C=CH₂), 3.76 (s, 1H, C=CH₂); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.36, −75.82; ¹³C NMR (101 MHz, CDCl₃) δ 161.1, 160.9, 139.8, 133.9, 133.5, 133.2, 132.8, 130.8, 130.8, 130.6, 130.5, 130.5, 130.3, 130.2, 130.2, 130.1, 123.0, 129.0, 128.3, 128.2, 127.9, 127.7, 125.5 (q, J_F–C = 286.84 Hz), 93.1, 92.9, 62.7, 62.5; HRMS (ESI) m/z calcd for C₁₈H₁₃ClF₃NO₂Na⁺ [M + Na]⁺ 390.0479 found 390.0478.

Data for 3c. Yellow solid, yield = 66.3%, mp 104–105 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.79 (dd, J = 6.5, 2.8 Hz, 2H, Ar-H), 7.53–7.41 (m, 5H, Ar-H), 7.22 (s, 1H, Ar-H), 7.12 (dt, J = 6.9, 2.1 Hz, 1H, Ar-H), 4.55 (d, J = 13.9 Hz, 1H, OCH₂), 4.48 (d, J = 13.9 Hz, 1H, OCH₂), 4.26 (s, 1H, C=CH₂), 3.88 (s, 1H, C=CH₂); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.86; ¹³C NMR (101 MHz, CDCl₃) δ 161.6, 140.8, 137.3, 135.4, 130.9, 130.2, 130.0, 129.3, 129.0, 129.0, 127.7, 127.0, 125.4 (q, J_F–C = 285.83 Hz), 93.9, 62.8; HRMS (ESI) m/z calcd for C₁₈H₁₃ClF₃NO₂Na⁺ [M + Na]⁺ 390.0479, found 390.0477.

Data for 3d. Yellow solid, yield = 43.8%, mp 109–112 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.79 (s, 2H, Ar-H), 7.54–7.43 (m, 5H, Ar-H), 7.15 (d, J = 7.5 Hz, 2H, Ar-H), 4.55 (d, J = 13.9 Hz, 1H, OCH₂), 4.48 (d, J = 13.9 Hz, 1H, OCH₂), 4.24 (s, 1H, C=CH₂), 3.87 (s, 1H, C=CH₂); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.89; ¹³C NMR (101 MHz, CDCl₃) δ 161.7, 141.0, 134.9, 134.7, 130.2, 130.1, 130.0, 129.0, 128.7, 127.7, 127.3, 125.5 (q, J_F–C = 286.84 Hz), 93.8, 62.8; HRMS (ESI) m/z calcd for C₁₈H₁₃ClF₃NO₂Na⁺ [M + Na]⁺ 390.0479, found 390.0474.

Data for 3e. White solid, yield = 51.8%, mp 112–113 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (dd, J = 6.3, 3.0 Hz, 2H, Ar-H), 7.50–7.42 (m, 3H, Ar-H), 7.29 (d, J = 8.1 Hz, 2H, Ar-H), 7.07 (d, J = 8.2 Hz, 2H, Ar-H), 4.53 (d, J = 13.9 Hz, 1H, C=CH₂), 4.47 (d, J = 13.9 Hz, 1H, OCH₂), 4.20 (s, 1H, OCH₂), 3.88 (s, 1H, C=CH₂), 2.40 (s, 3H, Ar-p-CH₃); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.85; ¹³C NMR (101 MHz, CDCl₃) δ 161.6, 141.2, 138.9, 133.6, 130.5, 130.4, 130.0, 128.9, 128.1, 127.8, 125.6 (q, J_F–C = 286.84 Hz), 93.6, 62.9, 21.2; HRMS (ESI) m/z calcd for C₁₉H₁₆F₃NO₂Na⁺ [M + Na]⁺ 370.1025, found 370.1022.

Data for 3f. White solid, yield = 89.3%, mp 98–100 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.84 (dd, J = 6.2, 2.8 Hz, 2H, Ar-H), 7.54–7.47 (m, 3H, Ar-H), 7.14 (d, J = 8.8 Hz, 2H, Ar-H), 7.03 (d, J = 8.9 Hz, 2H, Ar-H), 4.56 (d, J = 13.9 Hz, 1H, OCH₂), 4.50 (d, J = 13.9 Hz, 1H, OCH₂), 4.24 (s, 1H, C=CH₂), 3.92 (s, 1H, C=CH₂), 3.87 (s, 3H, Ar-p-OCH₃); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.87; ¹³C NMR (101 MHz, CDCl₃) δ 162.5, 160.3, 142.1, 131.1, 130.7, 130.1, 129.6, 129.4, 128.5, 126.2 (q, J_F–C = 286.84 Hz), 115.8, 94.2, 63.6, 56.2; HRMS (ESI) m/z calcd for C₁₉H₁₆F₃NO₃Na⁺ [M + Na]⁺ 386.0974, found 386.0976.

Data for 3g. Yellow solid, yield = 38.5%, mp 142–144 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J = 8.7 Hz, 2H, Ar-H), 7.83–7.75 (m, 2H, Ar-H), 7.56-7.42 (m, 5H, Ar-H), 4.61 (d, J = 14.0 Hz, 1H, OCH₂), 4.53 (d, J = 13.9 Hz, 1H, OCH₂), 4.34 (s, 1H, C=CH₂), 3.87 (s, 1H, C=CH₂); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.86; ¹³C NMR (101 MHz, CDCl₃) δ 161.6, 147.8, 142.0, 140.6, 133.1, 130.4, 130.0, 129.7, 129.1, 127.6, 125.3, 122.5 (q, J_F–C = 286.84 Hz), 94.2, 62.8; HRMS (ESI) m/z calcd for C₁₈H₁₃F₃N₂O₄Na⁺ [M + Na]⁺ 401.0720, found 401.0718.

Data for 3h. Yellow solid, yield = 47.0%, mp 135–136 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J = 8.2 Hz, 2H, Ar-H), 7.48 (d, J = 8.6 Hz, 2H, Ar-H), 7.28 (d, J = 8.2 Hz, 2H, Ar-H), 7.14 (d, J = 8.6 Hz, 2H, Ar-H), 4.53 (d, J = 13.9 Hz, 1H, OCH₂), 4.47 (d, J = 13.9 Hz, 1H, OCH₂), 4.22 (s, 1H, C=CH₂), 3.85 (s, 1H, C=CH₂), 2.40 (s, 3H, Ar-p-CH₃); ¹⁹F NMR (376 MHz, CDCl₃) δ −76.01; ¹³C NMR (101 MHz, CDCl₃) δ 161.8, 141.1, 140.3, 134.8, 134.7, 130.2, 130.0, 129.7, 129.6, 129.4, 127.6, 93.6, 62.7, 21.2; HRMS (ESI) m/z calcd for C₁₉H₁₅ClF₃NO₂Na⁺ [M + Na]⁺ 404.0636, found 404.0642.

Data for 3i. Yellow solid, yield = 37.8%, mp 150–151 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J = 8.9 Hz, 2H, Ar-H), 7.48 (d, J = 8.7 Hz, 2H, Ar-H), 7.14 (d, J = 8.6 Hz, 2H, Ar-H), 6.98 (d, J = 9.0 Hz, 2H, Ar-H), 4.52 (d, J = 13.9 Hz, 1H, OCH₂), 4.47 (d, J = 13.9 Hz, 1H, OCH₂), 4.23 (s, 1H, C=CH₂), 3.85 (s, 4H, C=CH₂ + Ar-p-OCH₃); ¹⁹F NMR (376 MHz, CDCl₃) δ −76.20; ¹³C NMR (101 MHz, CDCl₃) δ 162.6, 161.7, 141.8, 135.6, 135.4, 130.9, 130.7, 129.9, 122.4, 115.0, 94.3, 63.2, 56.0; HRMS (ESI) m/z calcd for C₁₉H₁₅ClF₃NO₃Na⁺ [M + Na]⁺ 420.0585, found 420.0567.

Data for 3j. Yellow solid, yield = 31.8%, mp 84–85 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J = 8.2 Hz, 2H, Ar-H), 7.48 (d, J = 8.6 Hz, 2H, Ar-H), 7.30 (d, J = 8.4 Hz, 2H, Ar-H), 7.15 (d, J = 8.6 Hz, 2H, Ar-H), 4.51 (s, 1H, OCH₂), 4.50 (s, 1H, OCH₂), 4.23 (s, 1H, C=CH₂), 3.85 (s, 1H, C=CH₂), 2.70 (q, J = 7.6 Hz, 2H, Ar-p-CH₂CH₃), 1.27 (t, J = 7.6 Hz, 3H, Ar-p-CH₂CH₃); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.97; ¹³C NMR (101 MHz, CDCl₃) δ 162.5, 147.2, 141.8, 135.6, 135.4, 130.9, 130.7, 130.0, 129.2, 128.4, 127.9, 94.2, 63.4, 29.2, 16.0; HRMS (ESI) m/z calcd for C₂₀H₁₇ClF₃NO₂Na⁺ [M + Na]⁺ 418.0792, found 418.0800.

Data for 3k. Yellow solid, yield = 32.9%, mp 97–99 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 8.8 Hz, 2H, Ar-H), 7.48 (d, J = 8.6 Hz, 2H, Ar-H), 7.39 (dd, J = 8.3, 7.6 Hz, 2H, Ar-H), 7.21–7.12 (m, 3H, Ar-H), 7.06 (t, J = 9.0 Hz, 4H, Ar-H), 4.54 (d, J = 13.9 Hz, 1H, OCH₂), 4.48 (d, J = 13.9 Hz, 1H, OCH₂), 4.26 (s, 1H, C=CH₂), 3.88 (s, 1H, C=CH₂); ¹⁹F NMR (376 MHz, CDCl₃) δ −76.08; ¹³C NMR (101 MHz, CDCl₃) δ 162.4, 160.0, 156.7, 141.6, 136.7, 135.6, 135.4, 130.9, 130.7, 130.6, 130.1, 125.0, 124.7, 120.6, 118.9, 94.5, 63.4; HRMS (ESI) m/z calcd for C₂₄H₁₇ClF₃NO₃Na⁺ [M + Na]⁺ 482.0741, found 482.0745.

Data for 3l. White solid, yield = 56.3%, mp 52–52 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 7.9 Hz, 2H, Ar-H), 7.69 (d, J = 7.7 Hz, 2H, Ar-H), 7.61 (d, J = 7.4 Hz, 2H, Ar-H), 7.48 (t, J = 9.4 Hz, 4H, Ar-H), 7.40 (d, J = 7.0 Hz, 1H, Ar-H), 7.17 (d, J = 7.6 Hz, 2H, Ar-H), 4.58 (d, J = 14.8 Hz, 1H, OCH₂), 4.51 (s, 1H, OCH₂), 4.27 (s, 1H, C=CH₂), 3.89 (s, 1H, C=CH₂); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.83; ¹³C NMR (101 MHz, CDCl₃) δ 161.7, 143.0, 140.9, 140.0, 134.9, 134.7, 130.2, 123.0, 129.0, 128.2, 127.9, 127.7, 127.2, 124.1, 121.2, 93.9, 62.9; HRMS (ESI) m/z calcd for C₂₄H₁₇ClF₃NO₂Na⁺ [M + Na]⁺ 466.0792, found 466.0798.

Fungicidal activities

The fungicidal activities of the synthesized compounds against Pseudoperonospora cubensis, Erysiphe graminis, Puccinia sorghi Schw (in vivo) and Pyricularia oryzae (in vitro) were determined as previously described.^24,25 The results are summarized in Tables 1 and 2.

Table 1 Fungicidal activities of the compounds prepared in the current study against Pseudoperonospora cubensis, Erysiphe graminis, Puccinia sorghi Schw (in vivo) and Pyricularia oryzae (in vitro)

No.	R^1	R^2	n	PC^a	EG	PS	PO
				400 mg L^−1			25 mg L^−1
a PC, Phytophthora capsici; EG, Erysiphe graminis; PS, Puccinia sorghi Schw; PO, Pyricularia oryzae.
2a	H	H	1	0	0	0	100
2b	4-F	H	1	0	100	80	50
2c	Me	H	1	95	0	0	80
2d	2-MeO	H	1	0	30	70	100
2e	4-MeO	H	1	0	0	50	100
2f	4-MeO	Et	1	40	0	0	0
2g	4-MeO	MeO	1	0	0	30	0
2h	4-MeO	Ph	1	30	0	0	0
2i	4-MeO	OPh	1	0	0	100	0
3a	4-F	H	0	0	0	80	0
3b	2-Cl	H	0	60	0	0	0
3c	3-Cl	H	0	0	98	80	50
3d	4-Cl	H	0	0	80	70	50
3e	4-Me	H	0	0	0	40	0
3f	4-MeO	H	0	0	30	0	0
3g	4-NO2	H	0	0	80	60	0
3h	4-Cl	Me	0	0	0	0	0
3i	4-Cl	MeO	0	0	0	0	0
3j	4-Cl	Et	0	0	0	0	0
3k	4-Cl	OPh	0	0	0	60	0
3l	4-Cl	Ph	0	0	0	0	0

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Table 2 Fungicidal activity against Pyricularia oryzae (in vitro)

No.	P. oryzae (mg L^−1)
	25	8.3	2.8	0.9
2a	100	100	50	0
2d	100	100	80	50
2e	100	80	80	50
Fenaminstrobin	100	100	100	80

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Conclusions

In conclusion, we have developed a facile and efficient method for the synthesis of a novel series of 5-methylenemorpholin-3-one derivatives by the reaction of trifluoroatrolactamides with propargyl bromide in the presence of sodium hydride. The subsequent evaluation of the fungicidal activities of these compounds revealed that some of them exhibited very good in vitro fungicidal activity against P. oryzae. Furthermore, the 5-methylenemorpholin-3-one ring structure of these compounds displayed a fine balance of stability and reactivity, which means that these systems could offer multiple structural optimization opportunities for finding new biologically active substances.

Acknowledgements

We are grateful for financial support for this work from the National Natural Science Foundation of China (21172124).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1427870 and 1427844. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra20138a

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