醋酸銨促進(jìn)烯胺酮的雙Michael加成反應(yīng)研究

葉青青, 陳浩宇, 謝吉娜, 何心偉

(1.滁州城市職業(yè)學(xué)院 醫(yī)學(xué)院,安徽 滁州 239000; 2.安徽師范大學(xué) 化學(xué)與材料科學(xué)學(xué)院,安徽 蕪湖 241002)

親核試劑對α,β-不飽和醛、酮等Michael受體的1,4-共軛加成作為C—X(X=C,N等)鍵構(gòu)建的重要方法在有機(jī)化學(xué)領(lǐng)域得到廣泛應(yīng)用,為重要有機(jī)分子或活性藥物分子的合成提供了簡便途徑[1-3].近年來,Michael加成反應(yīng)因具有強(qiáng)有力的合成能力而備受關(guān)注,有機(jī)催化的不對稱Michael加成反應(yīng)[4-6]、Michael加成/環(huán)化串聯(lián)反應(yīng)[7-9]等得到快速發(fā)展.此外,利用親核試劑對前驅(qū)體進(jìn)行雙Michael加成反應(yīng)為不對稱合成具有多個(gè)立體中心的復(fù)雜環(huán)狀化合物開辟了新途徑[10].

圖1 目標(biāo)化合物的合成路線Fig.1 Synthesis Route of Target Compounds

1 實(shí)驗(yàn)部分

1.1 試劑與儀器

BRUKER-AV-300型核磁共振儀(德國布魯克公司,300 MHz,CDCl3為溶劑,TMS為內(nèi)標(biāo));X-4 數(shù)字顯示顯微熔點(diǎn)測定儀(北京泰克儀器有限公司,溫度計(jì)未經(jīng)校正);Agilent 6200 LC/MS TOF 飛行時(shí)間質(zhì)譜儀(美國安捷倫公司).

所用溶劑和試劑均為分析純.

1.2 目標(biāo)化合物的合成

稱取81 mgN,N-二甲基烯胺酮(0.5 mmol)、112 mg 1,3-環(huán)己二酮(1.0 mmol)和57.75 mg醋酸銨(0.75 mmol)加入到裝有磁力攪拌子的Schlenk管中,再加入3 mL二氯乙烷并擰緊塞子.隨后置于油浴鍋中,加熱回流反應(yīng)40 min,利用薄層色譜(TLC)跟蹤反應(yīng),反應(yīng)結(jié)束后,冷卻至室溫.濃縮反應(yīng)液,先用10 mL飽和食鹽水洗滌,再分別用10 mL二氯甲烷萃取3次,接著用無水Na2SO4干燥2～3 h,濃縮濾液,最后通過柱層析分離得到目標(biāo)化合物3a.其他目標(biāo)化合物可由同樣方法制得.

1.3 產(chǎn)物表征數(shù)據(jù)

3,3-二(2-羥基-6-氧代-4,4-二甲基環(huán)己烯-1-基)-1-苯基丙-1-酮(3a):黃色固體,174 mg,收率85 %,熔點(diǎn)132～133 ℃.1HNMR(300 MHz,CDCl3)δ:12.49(s,1H),7.93(d,J=6.9 Hz,2H),7.52(d,J=6.9 Hz,1H),7.44(d,J=6.9 Hz,2H),4.80(s,1H),3.75(d,J=6.6 Hz,2H),2.26(s,8H),1.03(s,6H),0.98(s,6H);13CNMR(75 MHz,CDCl3)δ:198.1,190.5,189.4,136.8,133.0,128.5,128.0,116.4,46.9,46.1,38.6,31.1,29.8,26.3,24.3;IR(KBr)ν:2 947,2 831,2 656,1 679,1 632,1 499,1 335,1 224,1 156,916,745,606;HRMS(APCI) calcd for [C25H30O5+H]+411.198 6,found 411.199 0.

3,3-二(2-羥基-6-氧代-4,4-二甲基環(huán)己烯-1-基)-1-(4-甲基苯基)丙-1-酮(3b):黃色固體,182 mg,收率86 %,熔點(diǎn)112～113 ℃.1HNMR(300 MHz,CDCl3)δ:12.50(s,1H),7.83(d,J=7.2 Hz,2H),7.22(d,J=7.2 Hz,2H),4.82(s,1H),3.72(d,J=6.6 Hz,2H),2.39(s,3H),2.26(s,8H),1.03(s,6H),0.98(s,6H);13CNMR(75 MHz,CDCl3)δ:197.3,190.6,189.5,128.3,125.7,125.7,125.6,125.6,116.2,109.9,46.9,46.1,38.9,31.1,29.8,26.3,24.3;IR(KBr)ν:3 012,2 971,2 731,1 665,1 639,1 588,1 468,1 334,1 247,1 115,1 009,979,875,726,658;HRMS(APCI) calcd for [C26H32O5+H]+425.235 1,found 425.235 3.

3,3-二(2-羥基-6-氧代-4,4-二甲基環(huán)己烯-1-基)-1-(4-甲氧基苯基)丙-1-酮(3c):黃色固體,180 mg,收率82 %,熔點(diǎn)134～135 ℃.1HNMR(300 MHz,CDCl3)δ:12.49(s,1H),7.90(d,J=7.2 Hz,2H),6.89(d,J=7.2 Hz,2H),4.78(s,1H),3.83(s,3H),3.68(s,2H),2.25(s,8H),0.99(s,12H);13CNMR(75 MHz,CDCl3)δ:196.6,190.4,189.3,163.4,130.3,130.0,116.5,113.6,55.4,46.9,46.1,38.1,31.1,29.7,26.3,24.5;IR(KBr)ν:3 217,3 091,2 916,2 827,2 630,1 699,1 655,1 448,1 268,1 247,1 135,1 024,976,863,691;HRMS(APCI) calcd for [C26H32O6+H]+441.225 7,found 441.225 4.

3,3-二(2-羥基-6-氧代-4,4-二甲基環(huán)己烯-1-基)-1-(4-氟苯基)丙-1-酮(3d):黃色固體,194 mg,收率91 %,熔點(diǎn)118～119 ℃.1HNMR(300 MHz,CDCl3)δ:12.47(s,1H),7.96(s,2H),7.10(t,J=7.8 Hz,2H),4.79(t,J=6.0 Hz,1H),3.73(d,J=6.6 Hz,2H),2.26(s,8H),1.03(s,6H),0.97(s,6H);13CNMR(75 MHz,CDCl3)δ:196.5,190.5,189.4,165.7(d,JC-F=252.7 Hz),133.2,130.6(d,JC-F=9.0 Hz),116.3,115.6(d,JC-F=21.7 Hz),46.9,46.1,38.4,31.1,29.7,26.2,24.4;IR(KBr)ν:3 117,3 031,2 816,2 727,2 631,1 659,1 655,1 548,1 456,1 368,1 274,1 235,1 024,978,874,691;HRMS(APCI) calcd for [C25H29FO5+H]+429.198 9,found 429.198 6.

3,3-二(2-羥基-6-氧代-4,4-二甲基環(huán)己烯-1-基)-1-(4-溴苯基)丙-1-酮(3e):黃色固體,210 mg,收率86 %,熔點(diǎn)153～154 ℃.1HNMR(300 MHz,CDCl3)δ:12.47(s,1H),7.79(d,J=6.0 Hz,2H),7.58(s,2H),4.78(s,1H),3.72(s,2H),2.26(s,8H),1.03(s,6H),0.97(s,6H);13CNMR(75 MHz,CDCl3)δ:197.2,190.5,189.4,135.5,131.8,129.5,128.2,116.3,46.9,46.1,38.5,31.1,29.8,26.3,24.4;IR(KBr)ν:3 091,3 007,2 816,2 801,2 730,1 700,1 656,1 548,1 368,1 249,1 134,1 124,947,836,611;HRMS(APCI) calcd for [C25H29BrO5+H]+489.120 1,found 489.119 7.

3,3-二(2-羥基-6-氧代-4,4-二甲基環(huán)己烯-1-基)-1-(4-三氟甲基苯基)丙-1-酮(3f):黃色固體,203 mg,收率85 %,熔點(diǎn)158～159 ℃.1HNMR(300 MHz,CDCl3)δ:2.46(s,1H),8.06(d,J=7.2 Hz,2H),7.70(d,J=7.2 Hz,2H),4.80(s,1H),3.78(d,J=6.3 Hz,2H),2.27(s,8H),1.04(s,6H),0.98(s,6H);13CNMR(75 MHz,CDCl3)δ:197.3,190.6,189.5,128.3(q,J=25.5 Hz),125.6(q,J=254.4 Hz),116.2,109.99,46.9,46.1,38.9,31.1,29.8,26.3,24.3;IR(KBr)ν:2 936,2 846,2 651,1 691,1 553,1 432,1 345,1 279,1 171,1 054,997,864,715;HRMS(APCI) calcd for [C26H29F3O5+H]+479.201 7,found 479.202 0.

3,3-二(2-羥基-6-氧代-4,4-二甲基環(huán)己烯-1-基)-1-(3-氯苯基)丙-1-酮(3g):黃色固體,191 mg,收率86 %,熔點(diǎn)127～128 ℃.1HNMR(300 MHz,CDCl3)δ:12.47(s,1H),7.89(s,1H),7.81(d,J=7.2 Hz,1H),7.51(d,J=7.2 Hz,1H),7.38(t,J=7.2 Hz,1H),4.77(t,J=6.0 Hz,1H),3.73(d,J=6.6 Hz,2H),2.27(s,8H),1.04(s,6H),0.99(s,6H);13CNMR(75 MHz,CDCl3)δ:196.8,190.5,189.4,138.3,134.9,133.0,129.9,128.0,126.1,116.3,46.9,46.1,38.8,31.1,29.7,26.3,24.3;IR(KBr)ν:2 893,2 886,2 613,1 678,1 551,1 539,1 399,1 228,1 165,1 108,905,767,649;HRMS(APCI) calcd for [C25H29ClO5+H]+445.177 6,found 445.177 8.

3,3-二(2-羥基-6-氧代-4,4-二甲基環(huán)己烯-1-基)-1-(3-溴苯基)丙-1-酮(3h):黃色固體,207 mg,收率85 %,熔點(diǎn)118～119 ℃.1HNMR(300 MHz,CDCl3)δ:12.46(s,1H),8.04(s,1H),7.86(d,J=7.2 Hz,1H),7.67(d,J=7.2 Hz,1H),7.34～7.29(m,1H),4.77(s,1H),3.72(d,J=6.3 Hz,1H),2.27(s,8H),1.04(s,6H),0.99(s,6H);13CNMR(75 MHz,CDCl3)δ:196.8,190.5,189.4,138.5,135.9,130.2,126.5,122.9,116.3,46.8,46.1,38.7,31.11,29.8,26.3,24.3;IR(KBr)ν:2 931,2 816,2 789,1 691,1 576,1 443,1 368,1 243,1 109,1 088,907,767,649;HRMS(APCI) calcd for [C25H29BrO5+H]+489.120 3,found 489.119 9.

3,3-二(2-羥基-6-氧代-4-甲基環(huán)己烯-1-基)-1-苯基丙-1-酮(3i):黃色固體,158 mg,收率83 %,熔點(diǎn)109～110 ℃.1HNMR(300 MHz,CDCl3)δ:12.86(s,1H),7.92(d,J=6.6 Hz,2H),7.52(d,J=6.6 Hz,1H),7.44(d,J=6.9 Hz,2H),4.76(s,1H),3.72(d,J=6.3 Hz,2H),2.64～2.43(m,4H),2.35～2.14(m,2H),2.14～1.87(m,4H),1.01(s,6H);13CNMR(75 MHz,CDCl3)δ:198.1,191.9,190.7,136.8,133.0,128.5,128.0,117.3,41.6,40.9,38.9,38.7,27.4,24.6,24.5,20.5;IR(KBr)ν:2 999,2 847,2 676,1 690,1 663,1 599,1 501,1 488,1 326,1 247,1 154,965,823,773,689;HRMS(APCI) calcd for [C23H26O5+H]+383.167 8,found 383.168 2.

3,3-二(2-羥基-6-氧代-4-甲基環(huán)己烯-1-基)-1-(4-甲基苯基)丙-1-酮(3j):黃色固體,170 mg,收率86 %,熔點(diǎn)109～110 ℃.1HNMR(300 MHz,CDCl3)δ:12.86(s,1H),7.82(d,J=6.9 Hz,2H),7.22(d,J=6.6 Hz,2H),4.76(s,1H),3.68(d,J=7.2 Hz,2H),2.65～2.38(m,7H),2.24～2.13(m,2H),2.02～1.86(m,4H),1.01(s,6H);13CNMR(75 MHz,CDCl3)δ:197.7,191.8,190.6,143.8,134.1,129.2,128.1,117.4,41.6,40.9,38.7,38.6,27.5,27.4,24.6,24.5,21.6,20.4;IR(KBr)ν:3 324,3 016,2 901,2 784,2 731,1 696,1 559,1 474,1 318,1 245,1 185,1 103,974,862,689;HRMS(APCI) calcd for [C24H28O5+H]+397.194 5,found 397.194 2.

3,3-二(2-羥基-6-氧代-4-甲基環(huán)己烯-1-基)-1-(4-甲氧基苯基)丙-1-酮(3k):黃色固體,162 mg,收率79 %,熔點(diǎn)119～120 ℃.1HNMR(300 MHz,CDCl3)δ:12.86(s,1H),7.91(d,J=8.1 Hz,2H),6.90(d,J=8.1 Hz,2H),4.76(s,1H),3.85(s,3H),3.66(d,J=6.3 Hz,2H),2.62～2.46(m,4H),2.34～2.24(m,2H),2.16～1.85(m,4H),1.01(s,6H);13CNMR(75 MHz,CDCl3)δ:196.6,191.8,190.6,163.4,130.2,130.0,117.4,113.5,55.4,41.6,40.9,38.4,38.2,27.4,24.8,24.7,20.4;IR(KBr)ν:3 271,3 191,3 016,2 847,2 637,1 699,1 675,1 538,1 468,1 374,1 315,1 125,1 003,963,895,681;HRMS(APCI) calcd for [C24H28O6+H]+413.167 6,found 413.167 6.

3,3-二(2-羥基-6-氧代-4-甲基環(huán)己烯-1-基)-1-(4-氟基苯基)丙-1-酮(3l):黃色固體,178 mg,收率89 %,熔點(diǎn)125～126 ℃.1HNMR(300 MHz,CDCl3)δ:12.84(s,1H),7.94(s,1H),7.09(t,J=8.1 Hz,2H),4.74(s,1H),3.69～3.66(m,2H),2.64～2.43(m,4H),2.35～2.14(m,2H),2.02～1.82(m,4H),1.01(s,6H);13CNMR(75 MHz,CDCl3)δ:196.5,191.9,190.7,165.7(d,JC-F=253.5 Hz),133.2,130.6(d,JC-F=9.7 Hz),117.2,115.7(d,JC-F=21.7 Hz),41.6,40.9,38.7,38.6,29.6,27.5,27.4,24.6,24.5,20.4;IR(KBr)ν:3 213,2 991,2 916,2 727,2 531,1 703,1 659,1 648,1 568,1 547,1 335,1 024,996,873,655;HRMS(APCI) calcd for [C23H25FO5+H]+401.170 1,found 401.169 9.

3,3-二(2-羥基-6-氧代-4-甲基環(huán)己烯-1-基)-1-(4-溴苯基)丙-1-酮(3m):黃色固體,193 mg,收率84 %,熔點(diǎn)129～130 ℃.1HNMR(300 MHz,CDCl3)δ:12.83(s,1H),7.79(d,J=7.8 Hz,2H),7.57(d,J=8.1 Hz,2H),4.74(s,1H),3.68(d,J=6.6 Hz,2H),2.68～2.43(m,4H),2.24～2.13(m,2H),2.02～1.90(m,4H),1.02(s,6H);13CNMR(75 MHz,CDCl3)δ:197.1,191.9,190.7,135.5,131.8,129.5,128.2,117.2,41.6,40.9,38.8,38.6,29.7,27.5,27.4,24.6,24.5,20.4;IR(KBr)ν:3 217,3 119,3 011,2 782,2 630,1 694,1 565,1 544,1 368,1 257,1 235,1 124,1 083,865,676;HRMS(APCI) calcd for [C23H25BrO5+H]+461.097 5,found 461.097 9.

3,3-二(2-羥基-6-氧代-4-甲基環(huán)己烯-1-基)-1-(3-溴苯基)丙-1-酮(3n):黃色固體,193 mg,收率84 %,熔點(diǎn)142～143 ℃.1HNMR(300 MHz,CDCl3)δ:12.83(s,1H),8.03(s,1H),7.84(d,J=7.5 Hz,1H),7.66(d,J=6.9 Hz,1H),7.34～7.29(m,1H),4.72(s,1H),3.79(d,J=6.6 Hz,2H),2.61～2.36(m,4H),2.35～2.15(m,2H),2.15～1.90(m,4H),1.02(s,6H);13CNMR(75 MHz,CDCl3)δ:196.8,192.0,190.7,135.9,131.0,130.2,126.5,122.9,117.2,41.6,40.9,39.0,38.9,29.8,27.5,27.4,24.6,24.5,20.4;IR(KBr)ν:2 916,2 866,2 734,1 668,1 543,1 461,1 312,1 308,1 244,1 178,1 093,944,767,656;HRMS(APCI) calcd for [C23H25BrO5+H]+461.097 7,found 461.098 1.

3,3-二(2-羥基-6-氧代環(huán)己烯-1-基)-1-苯基丙-1-酮(3o):黃色固體,141 mg,收率80 %,熔點(diǎn)98～99 ℃.1HNMR(300 MHz,CDCl3)δ:12.90(s,1H),7.93(d,J=6.9 Hz,2H),7.53～7.43(m,3H),4.78(s,1H),3.73(d,J=6.0 Hz,2H),2.54～2.32(m,8H),1.86～1.78(m,2H);13CNMR(75 MHz,CDCl3)δ:198.2,192.0,190.9,136.8,133.0,128.5,128.0,117.6,39.0,33.3,32.6,24.7,19.9;IR(KBr)ν:3 065,2 974,2 701,1 685,1 609,1 548,1 478,1 347,1 251,1 095,990,871,762,684;HRMS(APCI) calcd for [C21H22O5+H]+355.158 7,found 355.159 0.

3,3-二(2-羥基-6-氧代環(huán)己烯-1-基)-1-(4-甲基苯基)丙-1-酮(3p):黃色固體,156 mg,收率85 %,熔點(diǎn)97～98 ℃.1HNMR(300 MHz,CDCl3)δ:12.90(s,1H),7.83(d,J=7.5 Hz,2H),7.23(d,J=7.5 Hz,2H),4.79(s,1H),3.70(d,J=6.3 Hz,2H),2.54～2.27(m,11H),1.99～1.69(m,4H);13CNMR(75 MHz,CDCl3)δ:197.8,192.0,190.9,143.8,134.4,129.2,128.1,117.7,38.8,33.3,32.6,24.7,21.6,19.8;IR(KBr)ν:3 189,3 062,2 961,2 901,2 631,1 657,1 499,1 448,1 368,1 352,1 217,1 145,1 092,919,889,674;HRMS(APCI) calcd for [C22H24O5+H]+369.153 1,found 369.153 6.

3,3-二(2-羥基-6-氧代環(huán)己烯-1-基)-1-(4-氟苯基)丙-1-酮(3q):黃色固體,148 mg,收率80 %,熔點(diǎn)103～104 ℃.1HNMR(300 MHz,CDCl3)δ:12.88(s,1H),8.06～7.87(m,2H),7.13～7.08(m,2H),4.78(s,1H),3.70(d,J=6.0 Hz,2H),2.55～2.28(m,8H),2.04～1.63(m,4H);13CNMR(75 MHz,CDCl3)δ:196.6,192.1,190.9,165.7(d,JC-F=252.7 Hz),133.3,130.6(d,JC-F=25.7 Hz),133.3,130(d,JC-F=9.7 Hz),117.6,115.7(d,JC-F=21.7 Hz),38.9,33.3,32.6,24.7,19.8;IR(KBr)ν:3 117,3 071,2 916,2 872,2 634,1 691,1 654,1 438,1 374,1 368,1 253,1 224,1 176,937,791,659;HRMS(APCI) calcd for [C21H21FO5+H]+373.154 3,found 373.154 7.

3,3-二(2-羥基-6-氧代環(huán)己烯-1-基)-1-(4-溴苯基)丙-1-酮(3r):黃色固體,181 mg,收率84 %,熔點(diǎn)101～102 ℃.1HNMR(300 MHz,CDCl3)δ:12.87(s,1H),7.79(d,J=7.5 Hz,2H),7.5(d,J=7.2 Hz,2H),4.77(s,1H),3.69(d,J=6.0 Hz,2H),2.55～2.32(m,4H),1.88～1.78(m,4H);13CNMR(75 MHz,CDCl3)δ:197.1,192.1,190.9,135.5,131.8,129.5,128.2,117.5,38.9,33.3,32.6,24.7,19.8;IR(KBr)ν:2 986,2 936,2 631,1 648,1 563,1 471,1 339,1 218,1 137,1 098,871,853;HRMS(APCI) calcd for [C21H21BrO5+H]+433.060 2,found 433.060 2.

3,3-二(2-羥基-6-氧代環(huán)己烯-1-基)-1-(3-溴苯基)丙-1-酮(3s):黃色固體,177 mg,收率82 %,熔點(diǎn)120～121 ℃.1HNMR(300 MHz,CDCl3)δ:12.87(s,1H),8.04(s,1H),7.85(d,J=7.8 Hz,1H),7.67(d,J=6.9 Hz,1H),7.33(d,J=6.9 Hz,1H),4.75(s,1H),3.70(d,J=6.3 Hz,2H),2.56～2.17(m,8H),2.00～1.66(m,4H);13CNMR(75 MHz,CDCl3)δ:196.8,192.2,190.9,135.9,131.0,130.1,126.5,122.9,117.5,39.1,33.3,32.6,24.6,19.8;IR(KBr)ν:3 016,2 976,2 866,1 654,1 604,1 564,1 551,1 477,1 340,1 253,1 201,1 118,1 062,967,867,748,659;HRMS(APCI) calcd for [C21H21BrO5+H]+433.060 4,found 433.060 1.

2 結(jié)果與討論

2.1 反應(yīng)條件優(yōu)化

為了優(yōu)化合成目標(biāo)產(chǎn)物3a的反應(yīng)條件,以N,N-二甲基烯胺酮(1a)和5,5-二甲基-1,3-環(huán)己二酮(2a)為模板底物,分別考察了堿、溶劑、反應(yīng)溫度和反應(yīng)時(shí)間對該反應(yīng)的影響,結(jié)果見表1.

2.1.1 堿的選擇

以1,2-二氯乙烷(DCE)為溶劑,在85 ℃、反應(yīng)時(shí)間為60 min的條件下,考察了堿的類型對3a產(chǎn)率的影響.結(jié)果表明:當(dāng)使用三乙烯二胺(DABCO)時(shí),反應(yīng)很難進(jìn)行,僅檢測到痕量的3a(見表1編號(hào)1);使用不同鹵化銨(NH4Cl,NH4Br,NH4I)時(shí),3a的產(chǎn)率分別為33 %,36 %,35 %(見表1編號(hào)2～4);使用碳酸銨或醋酸銨時(shí),3a的產(chǎn)率明顯提高,分別為75 %,81 %(見表1編號(hào)5,6).進(jìn)一步對醋酸銨的用量進(jìn)行了考察.與編號(hào)6相比,降低或增加醋酸銨的用量,3a的產(chǎn)率(45 %,48 %,78 %)均沒有增加(見表1編號(hào)7～9).研究還發(fā)現(xiàn),當(dāng)使用其他醋酸鹽(如醋酸鈉、醋酸鉀)作堿時(shí),僅能以63 %和53 %的產(chǎn)率得到3a(見表1編號(hào)10,11).

2.1.2 反應(yīng)溶劑的選擇

以醋酸銨(0.75 mmol)為堿,在85 ℃、反應(yīng)時(shí)間為60 min的條件下,對反應(yīng)溶劑進(jìn)行篩選.與1,2-二氯乙烷作溶劑時(shí)相比,溶劑為甲苯、1,4-二氧六環(huán)、四氫呋喃(THF)、乙醇、二氯甲烷(DCM)、水時(shí),3a的產(chǎn)率均明顯降低,分別為33 %,35 %,23 %,45 %,31 %,47 %(見表1編號(hào)12～17).

2.1.3 反應(yīng)溫度和反應(yīng)時(shí)間的選擇

采用最佳的醋酸銨用量,以1,2-二氯乙烷為溶劑,反應(yīng)時(shí)間為60 min,研究反應(yīng)溫度對3a產(chǎn)率的影響.結(jié)果顯示,降低溫度對反應(yīng)不利,當(dāng)反應(yīng)溫度降至45,60 ℃時(shí),3a的產(chǎn)率明顯降低,分別為37 %,67 %(見表1編號(hào)18,19).在最佳反應(yīng)溫度下,縮短反應(yīng)時(shí)間至20,40,50 min時(shí),3a的產(chǎn)率分別為44 %,82 %,81 %(見表1編號(hào)20～22);延長反應(yīng)時(shí)間至80 min時(shí),3a的產(chǎn)率略有降低,為76 %(見表1編號(hào)23).

因此,確定該反應(yīng)的最優(yōu)條件為:將0.75 mmol的醋酸銨作堿,1,2-二氯乙烷作溶劑,85 ℃下回流反應(yīng)40 min(見表1編號(hào)21).

表1 反應(yīng)條件的優(yōu)化aTab.1 Optimization of the Reaction Conditions

2.2 反應(yīng)底物的普適性

在最優(yōu)反應(yīng)條件下,進(jìn)一步對反應(yīng)底物的普適性進(jìn)行了探究,結(jié)果如圖2所示.首先以5,5-二甲基-1,3-環(huán)己二酮(2a)為底物,考察了N,N-二甲基烯胺酮(1)中苯環(huán)上取代基的電子效應(yīng)和空間位阻效應(yīng)對反應(yīng)的影響.結(jié)果顯示,當(dāng)苯環(huán)對位上連有中等強(qiáng)度的供電子基團(tuán)(-Me)或吸電子基團(tuán)(-F,-Br)時(shí),目標(biāo)產(chǎn)物的產(chǎn)率均能保持,3b,3d,3e的產(chǎn)率分別為81 %,86 %,85 %.當(dāng)苯環(huán)對位上連有強(qiáng)供電子基團(tuán)(-OMe)或強(qiáng)吸電子基團(tuán)(-CF3)時(shí),產(chǎn)物3c,3f的產(chǎn)率分別為75 %,81 %.當(dāng)苯環(huán)間位上連有取代基(—Cl,—Br)時(shí),該反應(yīng)也能很好地進(jìn)行,3g,3h的產(chǎn)率分別為86 %,85 %.此外,分別以5-甲基-1,3-環(huán)己二酮和1,3-環(huán)己二酮為底物,在標(biāo)準(zhǔn)條件下與各種取代的N,N-二甲基烯胺酮(1)反應(yīng)得到3,3-二環(huán)己烯基-1-苯基丙酮衍生物(3i～3s),產(chǎn)率為74 %～86 %.同樣地,目標(biāo)產(chǎn)物的產(chǎn)率不受底物取代基的電子效應(yīng)和空間位阻效應(yīng)的影響.為了確認(rèn)產(chǎn)物的結(jié)構(gòu),對化合物3f進(jìn)行了X射線單晶衍射表征,進(jìn)一步確證了目標(biāo)產(chǎn)物的結(jié)構(gòu).

圖2 目標(biāo)化合物3a～3s的分子結(jié)構(gòu)及3f的晶體結(jié)構(gòu)Fig.2 The Molecular Structures of Product 3a～3s and Crystal Structure of 3f

2.3 反應(yīng)機(jī)理

根據(jù)實(shí)驗(yàn)結(jié)果和文獻(xiàn)調(diào)研[21-23],以目標(biāo)產(chǎn)物3a的合成為例,對該反應(yīng)提出了一種可能的機(jī)理,如圖3所示.5,5-二甲基-1,3-環(huán)己二酮(2a)在醋酸銨的作用下發(fā)生烯醇異構(gòu)化生成中間體A,中間體A對N,N-二甲基烯胺酮(1a)進(jìn)行Michael加成反應(yīng)得到中間體B.由于氨基是一種較好的離去基團(tuán),中間體B在醋酸銨的作用下發(fā)生β-消除反應(yīng)離去二甲胺而生成中間體C.中間體A繼續(xù)與中間體C發(fā)生Michael加成反應(yīng)得到目標(biāo)產(chǎn)物3a.

圖3 可能的反應(yīng)機(jī)理Fig.3 A Possible Reaction Mechanism

3 結(jié) 論

發(fā)展了一種在醋酸銨作用下取代的1,3-環(huán)己二酮對取代的N,N-二甲基烯胺酮的雙Michael加成反應(yīng),合成了一系列結(jié)構(gòu)新穎的3,3-二環(huán)己烯基-1-苯基丙酮類化合物.該反應(yīng)在40 min內(nèi)能夠以優(yōu)異收率得到目標(biāo)產(chǎn)物,且所需原料廉價(jià)易得,實(shí)驗(yàn)操作簡單,在有機(jī)合成中具有潛在的應(yīng)用價(jià)值.