草地貪夜蛾性信息素的合成

王雪揚, 孫 效, 馬思捷, 原超楠, 袁谷城,邊慶花, 王 敏, 鐘江春

(中國農業大學 理學院 應用化學系 農藥創新中心，北京 100193)

0 Introduction

Spodoptera frugiperda(J. E, Smith), has caused substantial damage to various grain and forage crops throughout the Americans and has recently invaded into Africa and Asia[1]. This pest becomes very difficult to control because of its resistance to many insecticides includingBacillus thuringiensis(Bt)corns[2-3]. The sex pheromone technology is one of the most promising and environment-friendly strategies which can be used for monitoring, mating disruption,attracting and mass trapping ofS. frugiperda(J. E,Smith)[4].

The main active components ofS. frugiperda(J.E, Smith) sex pheromone have been isolated and identified asZenol acetates (1-4), (E)-dodec-7-en-1-yl acetate (5) and (9Z,12E)-tetradeca-9,12-dien-1-yl acetate (6) (Fig.1)[5]. The key to prepare these unsaturated esters is to constructZ- andE- double CC bonds. The main strategies for theZ-olefins involve the Lindlar hydrogenation of alkynes[6a-6b], olefin metathesis[7], deriving from methyl (Z)-hexadec-11-enoate or (Z)-2-butene-1,4-diol[8a], protonolysis or deiodoboronation of vinylic organoboranes[9]and the catalytic Shapiro reaction[10]. As for theE-olefins, the current methods are based on cyclopropane cleavage reaction[11], Grignard coupling of alkenyl halides[12],andE-materials such as methyl (E)-pent-3-enoate or(E)-pent-3-enenitrile[13-14a]. However, these reported approaches suffered from some limitations, such as expensiveZorEolefins, tedious synthetic sequences,or toxicity to environment.

To develop a more concise and efficient synthetic route ofS. frugiperda(J. E, Smith) sex pheromones, herein, we have disclosed the preparation of the unsaturated esters 1-6 based on the following key strategies: Wittig coupling of the aldehyde with functionalized phosphomium salt, the alkylation of alkynes, and Knoevenagel condensation reaction of malonic acid with propionic aldehyde(Schemes 1-4).

1 Experimental section

1.1 Instruments and reagents

All reactions were conducted under an argon atmosphere with Schlenk techniques unless indicated.Solvents were purified following the standard strategies, and other commercial reagents were used directly.1H and13C NMR spectra were collected on a Bruker DP-X300 MHz spectrometer with internal tetramethylsilane (TMS) for1H NMR and CDCl3for13C NMR. High resolution mass spectrometry (HMRS)data were recorded on an Agilent instrument with the TOF MS technique.

1.2 Experimental procedure

1.2.1 (7-Ethoxy-7-oxoheptyl)triphenylphosphonium bromide (8) In a three-neck 100-mL Schlenk flask,ethyl 7-bromoheptanoate (7) (2.371 g, 10.0 mmol),Ph3P (3.934 g, 15.0 mmol) and anhydrous toluene(30 mL) were added under an argon atmosphere at room temperature. The reaction mixture was heated to 110 °C and stirring for 24 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography(V(dichloromethane) :V(methanol) = 20 : 1) to provide (7-ethoxy-7-oxoheptyl)triphenylphosphonium bromide (8) (4.395 g, 88% yield) as a colorless oil.NMR characterization data for compound 8 were consistent with the literature data[15].

1.2.2 Ethyl (Z)-dodec-7-enoate (9) In a two-neck 50-mL Schlenk flask, the phosphomium salt 8 (1.498 g,3.0 mmol) and anhydrous tetrahydrofuran (THF)(10 mL) was added under an argon atmosphere at room temperature. The mixture was cooled to ?78 °C,and sodium bis (trimethylsilyl) amide (1.75 mL,2 mol/L in THF, 3.5 mmol) was then added over 25 min via syringe. The resulting mixture was stirred for 1 h at ?78 °C. After valeraldehyde (0.086 1 g,1.0 mmol) was added, the reaction mixture was allowed to warm slowly to room temperature and stirring overnight. The reaction was quenched with saturated NH4Cl aqueous solution (5 mL), and organic layer was separated. The aqueous phase was extracted with Et2O (3 × 10 mL), and the combined organic layers were dried over anhydrous Na2SO4.After filtering, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography(V(petroleum ether) :V(dichloromethane) = 120 : 1)to provide ethyl (Z)-dodec-7-enoate (9) (0.158 g, 70%yield) as a pale yellow oil.1H NMR (300 MHz,CDCl3),δ: 5.37?5.32 (m, 2H), 4.12 (q,J= 7.1 Hz,2H), 2.29 (t,J= 7.2 Hz, 2H), 2.02?2.00 (m, 4H),1.65?1.59 (m, 2H), 1.33?1.28 (m, 8H), 1.25 (t,J=7.2 Hz, 3H), 0.88 (t,J= 6.9 Hz, 3H).13C NMR (75 MHz, CDCl3),δ: 173.8, 130.1, 129.5, 60.1, 34.4,31.9, 29.4, 28.8, 27.0, 26.9, 24.9, 22.3, 14.2, 14.0. HRMS(APCI-TOF): calcd for C14H27O2[M+H]+227.201 1,found 227.200 6.

1.2.3 (Z)-Dodec-7-en-1-ol (10) In a two-neck 25-mL Schlenk flask, LiAlH4(0.114 g, 3.0 mmol) was placed under an argon atmosphere at room temperature.Anhydrous THF (5 mL) was added, and the resulting mixture was cooled to 0 °C. (Z)-Dodec-7-enoate (9)(0.226 g, 1.0 mmol) in THF (3 mL) was then added via syringe. The reaction mixture was allowed to warm slowly to room temperature and stirring overnight. The reaction was quenched with saturated NH4Cl aqueous solution (5 mL), and organic layer was separated. The aqueous phase was extracted with Et2O (3 × 5 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtering,the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (V(petroleum ether) :V(dichloromethane) = 120 : 1) to provide (Z)-dodec-7-en-1-ol (10) (0.162 g, 88% yield, 93%Zas determined by13C NMR) as a colorless oil.1H NMR(300 MHz, CDCl3),δ: 5.37?5.33 (m, 2H), 3.64 (t,J= 6.6 Hz, 2H), 2.03?2.01 (m, 4H), 1.61?1.53 (m,2H), 1.34?1.33 (m, 11H), 0.89 (t,J= 7.0, 3H).13C NMR (75 MHz, CDCl3),δ: 130.0, 129.7, 63.0, 32.8,31.9, 29.7, 29.0, 27.1, 26.9, 25.6, 22.3, 14.0. HRMS(APCI-TOF): calcd for C12H25O [M+H]+185.190 5,found 185.190 0. NMR characterization data for compound 10 were consistent with the literature data[16].

1.2.4 (Z)-Dodec-7-en-1-yl acetate (1) In a two-neck 50-mL Schlenk flask, anhydrous dichloromethane(DCM) (3 mL) and (Z)-dodec-7-en-1-ol (10) (0.184 g,1.0 mmol) and triethylamine (Et3N) (0.607 g,6.0 mmol) were added sequentially under an argon atmosphere at room temperature. The resulting mixture was cooled to 0 °C, acetyl chloride (0.236 g,3.0 mmol) in DCM (2 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for additional 8 h. The reaction was quenched with water (5 mL), and organic layer was separated. The aqueous phase was extracted with Et2O (3 × 5 mL), and the combined organic layers were dried over anhydrous Na2SO4.After filtering, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography(V(petroleum ether) :V(dichloromethane) = 80 : 1) to provide (Z)-dodec-7-en-1-yl acetate (1) (0.208 g, 92%yield, 93%Zas determined by13C NMR) as a pale yellow oil.1H NMR (300 MHz, CDCl3),δ: 5.37?5.33(m, 2H), 4.02 (t,J= 6.7 Hz, 2H), 2.04?2.01 (m, 7H),1.62?1.57 (m, 2H), 1.34?1.30 (m, 10H), 0.88 (t,J=6.9, 3H).13C NMR (75 MHz, CDCl3),δ: 171.0, 129.9,129.5, 64.5, 31.9, 29.5, 28.8, 28.5, 27.0, 26.8, 25.7,22.2, 20.8, 13.9. HRMS (APCI-TOF): calcd for C14H27O2[M+H]+227.201 2, found 227.200 6. NMR characterization data for compound 1 were consistent with the literature data[9b].

1.2.5 (9-Hydroxnonyl)triphenylphosphonium bromide (12a) In a three-neck 100-mL Schlenk flask, 9-bromononan-1-ol (11a) (1.000 g, 4.5 mmol)and Ph3P (1.760 g, 6.7 mmol), and MeCN (40 mL)were added under an argon atmosphere at room temperature. The reaction mixture was heated to reflux and stirring for 48 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography(V(petroleum ether) :V(dichloromethane) = 10 : 1) to afford (9-hydroxnonyl)triphenyl- phosphonium bromide (12a) as a pale yellow oil (1.980 g, 91%yield). HRMS (APCI-TOF): calcd for C27H35OBrNaP[M+Na]+508.150 1, found 508.120 2. NMR characterization data for compound 12a were consistent with the literature data[15].

1.2.6 (Z)-Dodec-9-en-1-ol (13) In a 250-mL Schlenk flask, phosphonium salt 12a (8.000 g, 16.5 mmol) and anhydrous THF (100 mL) were added under an argon atmosphere at room temperature. The mixture was cooled to ?78 °C, and sodium bis (trimethylsilyl)amide (16.5 mL, 2.0 mol/L in THF, 33.0 mmol) was then added dropwise via syringe. The resulting mixture was stirred for 1 h at ?78 °C. After propanal(1.920 g, 33.0 mmol) was added, the reaction mixture was allowed to warm to room temperature and stirred for 24 h. The reaction was quenched with saturated NH4Cl aqueous solution (40 mL), and organic layer was separated. The aqueous phase was extracted with Et2O (3 × 50 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtering,the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (V(petroleum ether) :V(dichloromethane) = 5 : 1) to provide (Z)-dodec-9-en-1-ol (13) (1.550 g, 51% yield, 97%Zas determined by13C-NMR) as a pale yellow oil.1H NMR (300 MHz, CDCl3),δ: 5.40?5.27 (m, 2H), 3.62(t,J= 6.7 Hz, 2H), 2.06?1.98 (m, 5H), 1.58?1.30 (m,12H), 0.95 (t,J= 7.5 Hz, 3H).13C NMR (75 MHz,CDCl3),δ: 131.5, 129.2, 62.8, 32.7, 29.7, 29.4, 29.4,29.1, 27.0, 25.7, 20.4, 14.3. HRMS (APCI-TOF):calcd for C12H25O [M+H]+185.190 0, found 185.190 1.NMR characterization data for compound 13 were consistent with the literature data[17a].

1.2.7 (Z)-Dodec-9-en-1-yl acetate (2) In a 100-mL Schlenk flask, anhydrous DCM (40 mL) and (Z)-dodec-9-en-1-ol (13) (1.471 g, 8.0 mmol) and Et3N(4.790 g, 47.3 mmol) were added sequentially under an argon atmosphere at room temperature. The resulting mixture was cooled to 0 °C, and acetic anhydride (2.420 g, 23.7 mmol) was added dropwise.The reaction mixture was allowed to warm to room temperature and stirred for additional 8 h. The reaction was quenched with water (20 mL), and organic layer was separated. The aqueous phase was extracted with DCM (3 × 30 mL), and the combined organic layers were dried over anhydrous Na2SO4.After filtering, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography(V(petroleum ether) :V(dichloromethane) = 80 : 1) to provide (Z)-dodec-9-en-1-yl acetate (2) (1.715 g, 95%yield, 97% Z as determined by13C NMR) as a pale yellow oil.1H NMR (300 MHz, CDCl3),δ: 5.56?5.10(m, 2H), 4.05 (t,J= 6.8 Hz, 2H), 2.06 (s, 3H),2.04?1.90 (m, 4H), 1.64?1.30 (m, 12H), 0.96 (t,J=6.5 Hz, 3H).13C NMR (75 MHz, CDCl3),δ: 171.1,131.5, 129.2, 64.6, 29.7, 29.3, 29.2, 29.1, 28.6, 27.0,25.9, 20.9, 20.5, 14.3. HRMS (APCI-TOF): calcd for C14H27O2[M+H]+227.200 6, found 227.200 8.1H NMR characterization data for compound 2 were consistent with the literature data[18a].

1.2.8 (Z)-Tetradec-9-en-1-ol (14) According to the similar procedure for the enol 13, the Wittig coupling of phosphonium salt 12a (8.000 g, 16.5 mmol) with pentanal (2.840 g, 33.0 mmol) provided (Z)-tetradec-9-en-1-ol (14) (2.327 g, 66% yield, 97%Zas determined by13C NMR) as a pale yellow oil.1H NMR (300 MHz,CDCl3),δ: 5.36?5.33 (m, 2H), 3.62 (t,J= 6.7 Hz,2H), 2.02?1.99 (m, 5H), 1.56?1.53 (m, 2H),1.35?1.30 (m, 14H), 0.90 (t,J= 7.1 Hz, 3H).13C NMR (75 MHz, CDCl3),δ: 129.8, 129.7, 62.8, 32.7,31.9, 29.7, 29.4, 29.3, 29.16, 27.1, 26.8, 25.7, 22.8,13.9. HRMS (APCI-TOF): calcd for C14H28ONa[M+Na]+235.203 2, found 235.204 0. NMR characterization data for compound 14 were consistent with the literature data[17a].

1.2.9 (Z)-Tetradec-9-en-1-yl acetate (3) According to the similar procedure for the sex pheromones 2, the esterification of (Z)-tetradec-9-en-1-ol (14) (2.228 g,10.5 mmol) with acetic anhydride (3.216 g, 31.5 mmol) gave (Z)-tetradec-9-en-1-yl acetate (3) (2.557 g,96% yield, 96%Zas determined by13C NMR) as a pale yellow oil.1H NMR (300 MHz, CDCl3),δ: 5.36?5.32 (m, 2H), 4.05 (t,J= 6.8 Hz, 2H), 2.04 (s, 3H),2.03?1.99 (m, 4H), 1.64?1.59 (m, 2H), 1.34?1.30 (m,14H), 0.90 (t,J= 7.0 Hz, 3H).13C NMR (75 MHz,CDCl3),δ: 171.0, 129.8, 129.7, 64.5, 31.9, 29.7, 29.3,29.2, 29.1, 28.6, 27.1, 26.8, 25.8, 22.3, 20.9, 13.9.HRMS (APCI-TOF): calcd for C16H30O2Na [M+Na]+277.213 8, found 277.214 2. NMR characterization data for compound 3 is consistent with the literature data[6b-6c].

1.2.10 (11-Hydroxundecyl)triphenylphosphonium bromide (12b) According to the similar procedure for the phosphonium salt 12a, the reaction of 11-bromoundecan-1-ol (11b) (0.502 g, 2.0 mmol) with Ph3P (0.787 g, 3.0 mmol) afforded (11-hydroxundecyl)triphenyl-phosphonium bromide (12b) as a pale yellow oil (0.849 g, 83% yield).1H NMR (300 MHz,CDCl3),δ: 7.86?7.71 (m, 15H), 3.60?3.55 (m, 4H),3.04 (brs, 1H), 1.62?1.47 (m, 6H), 1.27?1.19 (m,12H).13C NMR (75 MHz, CDCl3),δ:134.6, 134.5,133.0, 132.9, 130.1, 129.9, 118.1, 117.0, 61.7, 32.1,29.8, 29.6, 28.8, 28.7, 28.6, 28.4, 25.2, 22.5, 21.8.HRMS (APCI-TOF): calcd for C29H39OBrP [M+H]+513.191 6, found 513.178 8.1H NMR characterization data for compound 12b were consistent with the literature data[19].

1.2.11 (Z)-Hexadec-11-en-1-ol (15) According to the similar procedure for the enol 13, the Wittig coupling of phosphonium salt 12b (1.026 g, 2.0 mmol) with pentanal (0.120 g, 1.3 mmol) provided (Z)-hexadec-11-en-1-ol (15) (0.168 g, 54% yield, 97%Zas determined by13C NMR) as a pale yellow oil.1H NMR(300 MHz, CDCl3),δ: 5.36?5.33 (m, 2H), 3.62 (t,J=6.7 Hz, 2H), 2.17 (brs, 1H), 2.04?2.00 (m, 4H),1.60?1.50 (m, 2H), 1.35?1.28 (m, 18H), 0.90 (t,J=6.9 Hz, 3H).13C NMR (75 MHz, CDCl3),δ: 129.8,129.8, 62.9, 32.7, 31.9, 29.7, 29.6, 29.52, 29.48, 29.4,29.2, 27.1, 26.9, 25.7, 22.3, 13.9. HRMS (APCITOF): calcd for C16H32ONa [M+Na]+263.234 5, found 263.235 5.1H NMR characterization data for compound 15 were consistent with the literature data[20].

1.2.12 (Z)-Hexadec-11-en-1-yl acetate (4) According to the similar procedure for the sex pheromones 2, the esterification of (Z)-hexadec-11-en-1-ol (15) (0.103 g,0.43 mmol) with acetic anhydride (0.133 g, 1.3 mmol)afforded (Z)-hexadec-11-en-1-yl acetate (4) (0.114 g,94% yield, 96%Zas determined by13C NMR) as a pale yellow oil.1H NMR (300 MHz, CDCl3),δ: 5.35(t,J= 4.6 Hz, 2H), 4.05 (t,J= 6.8 Hz, 2H), 2.04 (s,3H), 2.01?1.99 (m, 3H), 1.64?1.57 (m, 2H),1.35?1.28 (m, 18H), 0.88 (t,J= 4.6 Hz, 3H).13C NMR (75 MHz, CDCl3),δ: 171.0, 129.8, 129.7, 64.6,31.9, 29.7, 29.49, 29.47, 29.46, 29.23, 29.21, 28.6,27.1, 26.9, 25.9, 22.3, 20.9, 13.9. HRMS (APCITOF): calcd for C18H34O2Na [M+Na]+305.245 1,found 305.246 5. NMR characterization data for compound 4 were consistent with the literature data[20].

1.2.13 2-((6-Bromohexyl)oxy)tetrahydro-2H-pyran(17) In a 20-mL Schlenk tube, 6-bromohexan-1-ol(16) (0.996 g, 5.5 mmol), dihydropyrane (0.950 g,11.0 mmol) and anhydrous DCM (10 mL) were added sequentially at room temperature.p-Toluenesulfonic acid (0.133 g, 1.3 mmol) was added dropwise,and the reaction mixture was stirred for 8 h at the same temperature. After the reaction was completed,it was washed with saturated Na2CO3aqueous solution(20 mL) and organic layer was separated. The aqueous phase was extracted with DCM (3 × 20 mL),and the combined organic layers were dried over anhydrous Na2SO4. After filtering, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (V(petroleum ether) :V(ethyl acetate) =80 : 1) to provide 2-((6-bromohexyl)oxy)tetrahydro-2H-pyran (17) (1.360 g, 93% yield) as a pale yellow oil. HRMS (APCI-TOF): calcd for C11H22O2Br[M+H]+265.079 8, found 265.079 8. NMR characterization data for compound 17 were consistent with the literature data[17c].

1.2.14 2-(Dodec-7-yn-1-yloxy)tetrahydro-2H-pyran(18) In a 50-mL Schlenk tube, hex-1-yne (0.790 g,9.6 mmol) and anhydrous THF (20 mL) were added under an argon atmosphere at room temperature. The mixture solution was cooled to ?48 °C,n-butyllithium(4 mL, 2.5 mol/L inn-hexane, 9.6 mmol) was added slowly and stirred for 2 h. 2-((6-bromohexyl)oxy)tetrahydro-2H-pyran (17) (1.270 g, 4.8 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred for 24 h.After the reaction was completed, it was cooled to 0 °C and quenched with water (2 mL). Organic layer was separated, and the aqueous phase was extracted with Et2O (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtering,the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (V(petroleum ether) :V(ethyl acetate) = 100 : 1) to generate 2-(dodec-7-yn-1-yloxy)tetrahydro-2H-pyran (18) (1.210 g, 95%yield) as a pale yellow oil.1H NMR (300 MHz, CDCl3),δ: 5.39?5.37 (m, 2H), 4.58 (t,J= 3.5 Hz, 1H),3.87?3.72 (m, 2H), 3.52?3.37 (m, 2H), 2.14?2.09 (m,4H), 1.83?1.38 (m, 18H), 0.91 (t,J= 7.1 Hz, 3H);13C NMR (75 MHz, CDCl3),δ: 98.8, 80.1, 80.0, 67.5,62.2, 31.2, 30.7, 29.6, 29.1, 28.6, 25.8, 25.5, 21.9,19.6, 18.6, 18.4, 13.5. HRMS (APCI-TOF): calcd for C17H31O2[M+H]+267.231 6, found 267.231 9.

1.2.15 (E)-2-(Dodec-7-en-1-yloxy)tetrahydro-2Hpyran (19) In a two-neck 100-mL Schlenk flask,LiAlH4(0.114 g, 3.0 mmol) and anhydrous diglyme(40 mL) were added under an argon atmosphere at room temperature. 2-(Dodec-7-yn-1-yloxy)tetrahydro-2H-pyran (18) (0.226 g, 1.0 mmol) was then added,and the reaction mixture was heated to reflux and stirring for 24 h. After the reaction was compledted, it was cooled to 0 °C. The reaction was quenched with saturated NH4Cl aqueous solution (3 mL) and MeOH(2 mL). The resulting mixture was filtered and rinsed with diethyl ether (30 mL). The combined filtrates were dried over anhydrous Na2SO4and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography(V(petroleum ether) :V(ethyl acetate) = 110 : 1) to provide (E)-2-(dodec-7-en-1-yloxy)tetrahydro-2Hpyran (19) (0.174 g, 65% yield, 88%Eas determined by13C NMR) as a pale yellow oil.1H NMR (300 MHz,CDCl3),δ: 5.40?5.37 (m, 2H), 4.58 (t,J= 3.5 Hz,1H), 3.87?3.72 (m, 2H), 3.52?3.36 (m, 2H),1.98?1.95 (m, 4H), 1.59?1.53 (m, 8H), 1.33?1.29 (m,10H), 0.89 (t,J= 6.9 Hz, 3H);13C NMR (75 MHz,CDCl3),δ: 130.4, 130.2, 98.8, 67.6, 62.3, 32.5, 32.3,31.8, 30.8, 29.7, 29.6, 29.0, 26.1, 25.5, 22.2, 19.7,13.9. HRMS (APCI-TOF): calcd for C17H33O2[M+H]+269.246 5, found 269.247 5.

1.2.16 (E)-Dodec-7-en-1-ol (20) In a 20-mL Schlenk tube, (E)-2-(dodec-7-en-1-yloxy)tetrahydro-2H-pyran (19) (0.268 g, 1.0 mmol) and MeOH (10 mL)were added at room temperature.p-Toluenesulfonic acid (0.180 g, 0.1 mmol) was then added, and the reaction mixture was stirred for 30 min at the same temperature. After the reaction was completed, it was quenched with saturated Na2CO3aqueous solution(3 mL) and organic layer was separated. The aqueous phase was extracted with DCM (3 × 20 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtering, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography((V(petroleum ether) :V(ethyl acetate) = 50 : 1) to provide (E)-dodec-7-en-1-ol (20) (0.158 g, 86% yield,88%Eas determined by13C NMR) as a colorless oil.1H NMR (300 MHz, CDCl3),δ: 5.39?5.33 (m, 2H),3.64 (t,J= 6.1 Hz, 2H), 2.03?1.98 (m, 4H),1.56?1.29 (m, 12H), 0.89 (t,J= 6.9 Hz, 3H);13C NMR (75 MHz, CDCl3),δ: 130.4, 130.1, 63.0, 32.7,32.5, 32.2, 31.8, 29.5, 28.9, 25.6, 22.2, 13.9. HRMS(APCI-TOF): calcd for C12H25O [M+H]+185.189 7,found 185.190 0. NMR characterization data for compound 20 were consistent with the literature data[9b].

1.2.17 (E)-Dodec-7-en-1-yl acetate (5) In a 20-mL Schlenk tube, anhydrous DCM (10 mL), (E)-dodec-7-en-1-ol (20) (0.184 g, 1.0 mmol) and Et3N (0.607 g,6.0 mmol) were added sequentially under an argon atmosphere at room temperature. The resulting mixture was cooled to 0 °C, acetyl chloride (0.236 g,3.0 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for additional 8 h. The reaction was quenched with water (5 mL), and organic layer was separated. The aqueous phase was extracted with DCM (3 × 10 mL),and the combined organic layers were dried over anhydrous Na2SO4. After filtering, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (V(petroleum ether) :V(ethyl acetate) =80 : 1) to provide (E)-dodec-7-en-1-yl acetate (5)(0.199 g, 88% yield, 88%Eas determined by13C NMR) as a colorless oil.1H NMR (300 MHz,CDCl3),δ: 5.40?5.37 (m, 2H), 4.05 (t,J= 6.8 Hz,2H), 2.05 (s, 3H), 2.03?1.96 (m, 4H), 1.63 –1.29 (m,12H), 0.89 (t,J= 7.0 Hz, 3H);13C NMR (75 MHz,CDCl3),δ: 171.2, 130.5, 130.1, 64.6, 32.5, 32.2, 31.8,29.5, 28.7, 28.6, 25.8, 22.2, 21.0, 13.9. HRMS (APCITOF): calcd for C14H27O2[M+H]+227.201 1, found 227.200 6. NMR characterization data for compound 5 were consistent with the literature data[9b].

1.2.18 (E)-Pent-3-enoic acid (22) In a 100-mL Schlenk flask, malonic acid (21) (10.406 g, 100.0 mmol), propionic aldehyde (2.904 g, 50.0 mmol) and dimethyl sulfoxide (DMSO) (40 mL) were added under an argon atmosphere at room temperature.Piperidine (0.042 6 g, 0.5 mmol) and acetic acid(0.030 0 g, 0.5 mmol) were added and the reaction mixture was stirred for 20 min at the same temperature. The reaction mixture was maintained for 2 h at 40 °C, and then was heated to 100 °C and stirred for additional 8 h. After the reaction mixture was cooled to room temperature, water (120 mL) was added. The resulting mixture was extracted with diethyl ether (3 × 100 mL), and the combined organic phases were dried over anhydrous Na2SO4. After filtering, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography(V(petroleum ether) :V(ethyl acetate) = 2 : 1) to provide (E)-pent-3-enoic acid (22) (3.495 g, 70%yield, 97%Eas determined by13C NMR) as a colorless oil.1H NMR (300 MHz, CDCl3),δ: 10.61 (s,1H), 5.68?5.47 (m, 2H), 3.07 (ddd,J= 4.5, 2.3, 1.3 Hz, 2H), 1.72?1.69 (m, 3H).13C NMR (75 MHz,CDCl3),δ: 178.8, 130.0, 121.9, 37.7, 17.8. HRMS(APCI-TOF): calcd for C5H8O2Na [M+Na]+123.041 7,found 123.0416. NMR characterization data for compound 22 were consistent with the literature data[21a].

1.2.19 (E)-Pent-3-en-1-ol (23) In a 100-mL Schlenk flask, LiAlH4(1.389 g, 36.6 mmol) and anhydrous THF (60 mL) were added at 0 °C under an argon atmosphere, a solution of (E)-pent-3-enoic acid(22) (2.823 g, 28.2 mmol) in THF (10 mL) was added. The reaction mixture was allowed to warm to room temperature over 10 min and then stirred for 8 h. The reaction was quenched with water (3 mL) at 0 °C, followed by the addition of 15% NaOH aqueous solution (3 mL) and water (5 mL). The resuting mixture was stirred for 1 h and filtered. The filtrate was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford (E)-pent-3-en-1-ol(23) (2.060 g, 85% yield, 97%Eas determined by13C NMR) as a colorless oil.1H NMR (300 MHz,CDCl3),δ: 5.60?5.38 (m, 2H), 3.61 (t,J= 6.4 Hz,2H), 2.28?2.21 (m, 2H), 2.17 (brs, 1H), 1.69?1.66(m, 3H).13C NMR (75 MHz, CDCl3),δ: 128.1, 127.1,61.9, 35.8, 17.9. HRMS (APCI-TOF): calcd for C5H10ONa [M+Na]+109.062 4, found 109.0648. NMR characterization data for compound 23 were consistent with the literature data[14a].

1.2.20 (E)-Bromo(pent-3-en-1-yl)triphenyl phosphane (24) In a 250-mL Schlenk flask, (E)-pent-3-en-1-ol (23) (1.998 g, 23.2 mmol), CBr4(11.540 g, 34.8 mmol) and anhydrous DCM (60 mL)were added under an argon atmosphere at room temperature. After cooling to 0 °C, triphenylphosphine(18.255 g, 69.6 mmol) in dry DCM (100 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for additional 5 h.After the reaction mixture was concentrated under reduced pressure, the residue was filtered and rinsed with diethyl ether (500 mL). The combined filtrates were concentrated under reduced pressure to give the crude product (E)-5-bromopent-2-ene (3.000 g).

In a 100-mL Schlenk flask, the crude (E)-5-bromopent-2-ene (0.999 g, 6.7 mmol) and dry acetonitrile (60 mL) were added at room temperature under an argon atomosphere. Triphenylphosphine(2.649 g, 10.1 mmol) was then added, and the resulting mixture was refluxed for 48 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (V(chloromethane) :V(methanol) =10 : 1) to provide (E)-bromo(pent-3-en-1-yl) triphenyl phosphane (24) (1.748 g, 58% yield over two steps)as a colorless oil.1H NMR (300 MHz, CDCl3),δ:7.87?7.69 (m, 15H), 5.58?5.41 (m, 2H), 3.82?3.73(m, 2H), 2.47?2.36 (m, 2H), 1.55?1.52 (m, 3H).13C NMR (75 MHz, CDCl3),δ: 134.9, 134.9, 133.5,133.4, 130.4, 130.3, 127.4, 127.2, 118.5, 117.4, 25.4,23.1, 17.4. HRMS (APCI-TOF): calcd for C23H25BrP[M+H]+411.087 2, found 411.088 3. NMR characterization data for compound 24 were consistent with the literature data[14a].

1.2.21 9-Bromononanal (25) In a 250-mL Schlenk flask, pyridinium chlorochromate (8.687 g, 40.3 mmol), silica gel (8.690 g) and anhydrous DCM(70 mL) were added under an argon atmosphere at room temperature. The resulting mixture was cooled to 0 °C and 9-bromononan-1-ol (11a) (2.990 g, 13.4 mmol) in anhydrous DCM (20 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stired for 4 h. After the reaction was completed, DCM was removed under reduced pressure. The residue was filtered and rinsed with diethyl ether (500 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (V(petroleum ether) :V(ethyl acetate) =40 : 1) to provide 9-bromononanal (25) (2.448 g, 83%yield) as a pale yellow oil. HRMS (APCI-TOF): calcd for C9H18OBr [M+H]+221.053 6, found 221.054 4.NMR characterization data for compound 25 were consistent with the literature data[22a].

1.2.22 9-Oxononyl acetate (26) In a 50-mL Schlenk flask, KOAc (2.081 g, 21.2 mmol) and dimethyl formamide (DMF) (20 mL) were added at room temperature. 9-Bromononanal (25) (2.344 g,10.6 mmol) was then added, and the resulting mixture was heated to 120 °C and stirred for 2 h. After the reaction was completed, it was poured into water(100 mL) and extracted with diethyl ether (3 ×50 mL). The combined organic layers were washed with water (3 × 100 mL), and dried over anhydrous Na2SO4. After filtering, the filtrate was concentrated under reduced pressure to give 9-oxononyl acetate(26) (1.514 g, 71% yield) as a colorless oil. HRMS(APCI-TOF): calcd for C11H21O3[M+H]+201.148 5,found 201.148 5. NMR characterization data for compound 26 were consistent with the literature data[22a].

1.2.23 (9Z,12E)-Tetradeca-9,12-dien-1-yl acetate(6) In a 100-mL Schlenk flask, phosphonium salt 24(1.686 g, 4.1 mmol) and anhydrous THF (40 mL)were added under an argon atmosphere at room temperature. The mixture was cooled to ?78 °C, and sodium bis(trimethylsilyl)amide (2.1 mL, 2 mol/L in THF, 4.2 mmol) was then added dropwise via syringe. The resulting mixture was stirred for 1 h at?78 °C. After aldehyde 26 (0.821 g, 4.1 mmol) was added, the reaction mixture was allowed to warm slowly to room temperature and stirred for 24 h. The reaction was quenched with saturated NH4Cl aqueous solution (20 mL), and organic layer was separated.The aqueous phase was extracted with Et2O (3 ×30 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtering, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (V(petroleum ether) :V(dichloromethane) = 80 : 1) to provide (9Z,12E)-tetradeca-9, 12-dien-1-yl acetate (6) (0.578 g, 56%yield) as a pale yellow oil.1H NMR (300 MHz,CDCl3),δ: 5.46?5.30 (m, 4H), 4.05 (t,J= 6.8 Hz,2H), 2.73?2.69 (m, 2H), 2.04 (s, 3H), 2.02?1.99 (m,2H), 1.66?1.64 (m, 5H), 1.36?1.30 (m, 10H).13C NMR (75 MHz, CDCl3),δ: 171.1, 130.3, 129.6,127.6, 125.0, 64.5, 30.4, 29.6, 29.3, 29.2, 29.1, 28.6,27.0, 25.8, 20.9, 17.8. HRMS (APCI-TOF): calcd for C16H29O2[M+H]+253.216 2, found 253.216 1. NMR characterization data for compound 6 were consistent with the literature data[14a].

2 Results and discussion

Our research started from the preparation of the sex pheromone 1 (Scheme 1). The initial step was the synthesis of ester-bearing phosphomium salt 8 from ethyl 7-bromoheptanoate (7) with 88% yield[14].Subsequent Wittig coupling with valeraldehyde in the presence of sodium bis(trimethylsilyl)amide afforded ethyl (Z)-dodec-7-enoate (9)[15]. Its configuration of the double bond was assigned asZ, according to the intense resonances atδ27.0 and 26.9, which matched the expected chemical shifts of the allylic carbons of aZ-double bond[17b]. Furthermore, the NMR characterization data of the reduced product of 9 were consistent with the literature data[16]for (Z)-dodec-7-en-1-ol (10), and it supported the confirmation toZdouble configuration of 9. The following esterification with acetyl chloride generated the sex pheromone 1 in 92% yield[9b].

We next investigated the preparations of three sex pheromones 2-4 (Scheme 2). To optimize the synthesis of theseZenol acetates, we tried hydroxybearing phosphomium salt in Wittig couplings of aldehydes because this method save the protection and the subsequent deprotection[18b]. Fortunately, the desiredZenols 13-15 were obtained from phosphomium salts 12a and 12b[15], which were synthesized by the reaction of bromo alcohol 11 and Ph3P[19].There were two evidences to support the confirmation toZdouble configuration of enols 13-15. NMR characterization data for theseZenols matched the literature data[20]. Meanwhile, their chemical shifts of the allylic carbons were consist with the expected ones[17b]. The final esterification with acetic anhydride afforded the target sex pheromones 2-4 almost quantitatively[21b].

Next, the sex pheromones 5 were synthesized(Scheme 3). In the presence ofn-BuLi, the alkylation of hex-1-yne with tetrohydropyran(THP)-protected bromo alcohol 17 derived from 6-bromohexan-1-ol(16) afforded 2-(dodec-7-yn-1-yloxy)tetrahydro-2Hpyran (18) in 95% yield[22b]. The THP-protected alkynol 18 was then reduced to (E)-2-(dodec-7-en-1-yloxy)tetrahydro-2H-pyran (19) with LiAlH4in diglyme[23], and the assignment of itsEdouble bond according to the consistence of its NMR spectra with the literature one[24]and the expected chemical shifts[17b]. After the deprotection withptoluenesulfonic acid[8b],Zenol 20 was esterified to the desired sex pheromone 5 with acetyl chloride in CH2Cl2[9b].

Finally, we prepared the sex pheromone 6(Scheme 4). TheEdouble bond was constructed by Knoevenagel condensation reaction of malonic acid(21) with propionic aldehyde, and (E)-pent-3-enoic acid (22) was obtained in 70% yield[25]. Acid 22 was reduced to (E)-pent-3-en-1-ol (23) with LiAlH4in THF[26], and its NMR spectra was consistent with the literature data[14a]. Subsequent bromination and the reaction with PPh3generated phosphomium salt 24 in 58% yield in two steps[14a]. The other key intermediate 26 was then prepared. The oxidation of bromo alcohol 11a with pyridinium chlorochromate furnished 9-bromononanal (25) in 83% yield[27]. Treating aldehyde 25 with KOAc resulted in the formation of 9-oxononyl acetate (26) in 71% yield[13].ZDouble bond was formed via the Wittig coupling of aldehyde 26 with phosphomium salt 24, and the target sex pheromones 6 was obtained[15]. Its NMR spectra were identical to the reported one[13].

3 Conclusions

In summary, we have developed a novel, efficient and concise synthesis ofS. frugiperda(J. E, Smith) sex pheromones. The synthetic approaches mainly include Wittig coupling of aldehyde with functionalized phosphomium salt, the alkylation of alkynes, and Knoevenagel condensation reaction of malonic acid with propionic aldehyde. It is noteworthy that this work is the first synthesis ofS. frugiperda(J. E,Smith) sex pheromones via Knoevenagel condensation reaction and the Wittig reaction of hydroxy-bearing phosphomium salt, which could save the protection and the subsequent deprotection.