手性伯胺催化麥克爾/烷基化串聯(lián)反應(yīng)：螺靛紅環(huán)丙烷衍生物的高效合成*

謝建武， 余超波， 徐美蘭

(浙江師范大學(xué) 化學(xué)與生命科學(xué)學(xué)院,浙江 金華 321004)

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手性伯胺催化麥克爾/烷基化串聯(lián)反應(yīng)：螺靛紅環(huán)丙烷衍生物的高效合成*

謝建武， 余超波， 徐美蘭

(浙江師范大學(xué) 化學(xué)與生命科學(xué)學(xué)院,浙江 金華 321004)

為了合成同時(shí)具有環(huán)丙烷和靛紅骨架的化合物，通過(guò)手性伯胺催化麥克爾/烷基化反應(yīng)，得到了一種高效、溫和及方便合成螺靛紅環(huán)丙烷衍生物的方法.在優(yōu)化的條件下：烯酮與溴代丙二酸乙酯在手性伯胺/碳酸銫的催化下，以二氯甲烷為溶劑，常溫下反應(yīng)48 h，以47%～97%的收率獲得了一系列的螺靛紅環(huán)丙烷衍生物.

麥克爾加成；烷基化反應(yīng)；環(huán)丙烷；靛紅

靛紅骨架單元常存在于很多生物堿和醫(yī)藥相關(guān)的化合物中[1-2]，具有顯著的生物活性.此外，靛紅本身在不同的pH條件下有多種互變異構(gòu)，具有很高的活性.因此，靛紅常作為合成中間體被廣泛應(yīng)用在醫(yī)藥、農(nóng)藥、染料和精細(xì)化工等方面[3-5].所以，這類(lèi)化合物引起了人們廣泛的合成興趣.近年來(lái)，化學(xué)家們對(duì)靛紅的應(yīng)用做了深入的研究，并取得了一些重要的結(jié)果.從1982年到2014年，以靛紅為中間體的研究成果中，大部分為專(zhuān)利，約有963篇，占總數(shù)的72.5%；其次為涉及到以靛紅為中間體的合成、藥理和活性研究論文，約有294篇，占總數(shù)的22.2%；其余的研究成果占總數(shù)的5.3%.其中，涉及專(zhuān)利的研究成果絕大部分都跟藥理、活性等有關(guān)系.可見(jiàn)，靛紅是一個(gè)非常重要的醫(yī)藥、化工中間體.

圖1 以靛紅為骨架單元合成的具有活性的物質(zhì)

螺環(huán)化合物是兩平面互相垂直且具有特殊剛性結(jié)構(gòu)的化合物，其雜環(huán)類(lèi)的衍生物作為一類(lèi)具有特殊結(jié)構(gòu)的雜環(huán)廣泛地存在眾多的天然產(chǎn)物中.由于螺環(huán)類(lèi)化合物具有分子量小、所占空間體積較大的特點(diǎn)，計(jì)算機(jī)模擬顯示含有這類(lèi)化合物的分子往往具有各種各樣的藥物及生物活性[6].近十年來(lái)，化學(xué)家們以靛紅為骨架合成了一系列螺靛紅雜環(huán)化合物，部分化合物被證明有良好的生物活性[7](見(jiàn)圖1).三元環(huán)化合物是許多天然產(chǎn)物和藥物的骨架[8-10]；此外，它還是高效、有價(jià)值的合成中間體，開(kāi)環(huán)增大碳鏈后可以形成復(fù)雜的雜環(huán)化合物[11-12].靛紅衍生物構(gòu)建的單螺三元環(huán)化合物，不但有著螺環(huán)羥吲哚生物堿的性質(zhì)，更有著復(fù)雜的結(jié)構(gòu)和優(yōu)越的生物活性，是構(gòu)成天然產(chǎn)物和合成藥物的重要骨架.本文以靛紅衍生的烯酮為原料，在手性伯胺的催化下，與溴代丙二酸二乙酯發(fā)生麥克爾-烷基化串聯(lián)反應(yīng)，高效、高選擇性地合成了螺靛紅環(huán)丙烷衍生物.

1 實(shí)驗(yàn)部分

1.1 試劑與儀器

WRS-1B數(shù)字熔點(diǎn)儀(溫度計(jì)未經(jīng)校正)；WZZ-2B自動(dòng)旋光儀；Bruker Avance 400型或600型核磁共振波譜儀(二甲基亞砜或CDCl3為溶劑，三甲基硅為基準(zhǔn)物質(zhì))；美國(guó)Waters 1525高效液相色譜儀;德國(guó)Bruker高分辨質(zhì)譜儀(BioTOFⅢQ).

有機(jī)反應(yīng)用薄層硅膠色譜(TLC)跟蹤監(jiān)測(cè).

1.2 1,3-質(zhì)子遷移反應(yīng)的一般步驟

不飽和酮(0.12 mmol)、溴代丙二酸酯(0.12 mmol)、催化劑(0.02 mmol)及碳酸銫(0.12 mmol)溶于1 mL二氯甲烷中，25 ℃反應(yīng)48 h(見(jiàn)圖2).經(jīng)快速柱色譜(流動(dòng)相：V(乙酸乙酯)/V(石油醚)=1/4)分離得到對(duì)應(yīng)的螺靛紅環(huán)丙烷衍生物.

圖2 螺靛紅環(huán)丙烷衍生物的合成

2 結(jié)果與討論

2.1 反應(yīng)條件的優(yōu)化

以烯酮(見(jiàn)圖2:R=CH3,Ar=C6H5)和溴代丙二酸酯為反應(yīng)模板，對(duì)反應(yīng)條件進(jìn)行了優(yōu)化.

直接以氫氧化鈉催化該麥克爾-烷基化串聯(lián)反應(yīng)時(shí)，可以獲得螺靛紅環(huán)丙烷衍生物，但是非對(duì)映選擇性非常差(見(jiàn)表1:編號(hào)1).加入金雞納堿手性催化劑(見(jiàn)圖3)后，產(chǎn)物的收率及非對(duì)映選擇性得到顯著提高.如，加入奎寧(見(jiàn)圖3：Ⅰ)、辛克寧(見(jiàn)圖3：Ⅱ)或者季銨鹽(見(jiàn)圖3：Ⅲ)，產(chǎn)物的收率及非對(duì)映選擇性都有很大程度的提高，但是并不滿(mǎn)意(見(jiàn)表1：編號(hào)2-4).幸運(yùn)的是，當(dāng)加入手性伯胺(見(jiàn)圖3：Ⅳ)時(shí)，螺靛紅環(huán)丙烷衍生物的收率及非對(duì)映選擇性都非常好，收率達(dá)到84%，而且非對(duì)映選擇性為97∶3(見(jiàn)表1：編號(hào)5).

圖3 手性催化劑Ⅰ～Ⅳ

編號(hào)催化劑/堿溶劑產(chǎn)率/%非對(duì)映選擇性1-/NaOHCH2Cl24554∶462Ⅰ/NaOHCH2Cl25162∶383Ⅱ/NaOHCH2Cl26059∶414Ⅲ/NaOHCH2Cl27175∶255Ⅳ/NaOHCH2Cl28497∶36Ⅳ/Na2CO3CH2Cl2--7Ⅳ/Cs2CO3CH2Cl272>99∶18Ⅳ/DBUCH2Cl2--9Ⅳ/Cs2CO3CH3CH2OH7778∶2210Ⅳ/Cs2CO3THF6587∶1311Ⅳ/Cs2CO3CH3COCH36990∶10

于是，以手性伯胺為催化劑繼續(xù)篩選堿.通過(guò)篩選，碳酸銫表現(xiàn)非常好，獲得了大于99∶1的非對(duì)映選擇性(見(jiàn)表1：編號(hào)7).對(duì)于有機(jī)堿，該反應(yīng)基本上不進(jìn)行.最后，對(duì)其他溶劑，如乙醇、乙腈、丙酮和四氫呋喃(THF)也進(jìn)行了篩選，但無(wú)論是產(chǎn)率還是非對(duì)映選擇性都明顯地下降.

根據(jù)以上的條件篩選，得到該麥克爾-烷基化串聯(lián)反應(yīng)的優(yōu)化條件為：烯酮與溴代丙二酸乙酯在手性伯胺/碳酸銫的催化下，以二氯甲烷為溶劑，常溫下反應(yīng)48 h.

2.2 反應(yīng)底物的擴(kuò)展

根據(jù)上述優(yōu)化條件，分別對(duì)有各種取代基的靛紅衍生的烯酮底物進(jìn)行了適用性研究，實(shí)驗(yàn)結(jié)果見(jiàn)表2.

烯酮的N上取代基為甲基時(shí)，芳環(huán)上取代基的電子效應(yīng)對(duì)產(chǎn)物的產(chǎn)率及非對(duì)映選擇性有非常大的影響.芳環(huán)上有供電子基團(tuán)，如甲基、甲氧基時(shí)，都可以獲得優(yōu)秀的非對(duì)映選擇性，但是產(chǎn)物的收率偏低(見(jiàn)表2：編號(hào)2-3)；反之，芳環(huán)上有拉電子基團(tuán)，如氯、溴時(shí)，非對(duì)映選擇性有所降低，但是產(chǎn)物的收率卻很好(見(jiàn)表2：編號(hào)4-7).此外，芳環(huán)鄰位有取代基時(shí)，對(duì)非對(duì)映選擇性的影響非常大，僅僅得到70∶30的非對(duì)映選擇性.當(dāng)烯酮N上的取代基為芐基時(shí)，芳環(huán)上無(wú)論是供電子基團(tuán)還是拉電子基團(tuán)，都能獲得較好的非對(duì)映選擇性.但是，烯酮N上的取代基為H時(shí)，芳環(huán)上有拉電子基團(tuán)時(shí)產(chǎn)物的非對(duì)映選擇性明顯低于芳環(huán)上有供電子基團(tuán)者.

2.3 反應(yīng)產(chǎn)物的表征

產(chǎn)物3aa 淡黃色固體；熔點(diǎn):140～141 ℃;IR(KBr)σ/cm-1:3 062,2 980,1 741,1 719,1 589,1 470,1 245,1 176,967,830;1H NMR(600 MHz,CDCl3)δ:8.17(dd,J=8.1,0.8 Hz,2H),7.58(t,J=7.4 Hz,1H),7.48(t,J=7.7 Hz,2H),7.36(d,J=7.7 Hz,1H),7.34～7.30(m,1H),7.03(t,J=7.7 Hz,1H),6.91(d,J=7.8 Hz,1H),4.33(dd,J=7.1,5.7 Hz,2H),4.14(dd,J=7.1,4.4 Hz,2H),4.06(s,1H),3.29(s,3H),1.33(t,J=7.1 Hz,3H),1.13(t,J=7.1 Hz,3H);13C NMR(150 MHz,CDCl3)δ:190.3,171.6,165.1,163.6,144.7,136.6,133.7,128.7,128.5,127.0,122.2,120.9,108.3,62.5,48.7,41.1,40.4,26.9,14.0,13.8；高分辨質(zhì)譜m/z：計(jì)算值C24H23NNaO6+[M+Na+] 444.141 8,測(cè)量值444.141 9.

表2 底物的擴(kuò)展

產(chǎn)物3ab 淡黃色固體；熔點(diǎn):126～127 ℃;IR(KBr)σ/cm-1:3 062,2 979,1 740,1 718,1 574,1 467,1 246,1 173,961,836,760,691;1H NMR(600 MHz,CDCl3)δ:8.13(d,J=8.9 Hz,2H),7.37(dd,J=7.7,0.7 Hz,1H),7.31(td,J=7.7,1.2 Hz,1H),7.02(td,J=7.7,1.0 Hz,1H),6.93(d,J=8.9 Hz,2H),6.90(d,J=7.8 Hz,1H),4.36～4.27(m,2H),4.16(d,J=7.1 Hz,2H),4.03(s,1H),3.86(s,3H),3.29(s,3H),1.32(t,J=7.1 Hz,3H),1.15(t,J=7.1 Hz,3H);13C NMR(150 MHz,CDCl3)δ:188.7,171.7,165.2,163.9,163.7,144.6,130.8,129.8,128.6,127.1,122.2,121.0,113.9,108.2,62.4,55.5,48.5,41.1,40.4,26.8,14.0,13.8；高分辨質(zhì)譜m/z：計(jì)算值C25H25NNaO7+[M+Na+] 474.152 3,測(cè)量值474.152 0.

產(chǎn)物3ac 淡黃色固體；熔點(diǎn):69～73 ℃;IR(KBr)σ/cm-1:3 372,3 070,2 981,1 736,1 695,1 597,1 490,1 473,1 221,908,807,748,689;1H NMR(400 MHz,CDCl3)δ:8.46(s,1H),8.06(d,J=8.2 Hz,2H),7.36(d,J=7.8 Hz,1H),7.28(t,J=4.0 Hz,4H),6.98(dd,J=28.9,7.8 Hz,2H),4.33(dd,J=11.5,7.1 Hz,2H),4.18(dd,J=11.2,4.8 Hz,2H),4.06(s,1H),2.42(s,3H),1.33(t,J=7.1 Hz,3H),1.18(t,J=7.1 Hz,3H);13C NMR(150 MHz,CDCl3)δ:189.7,173.8,165.2,163.5,144.7,141.7,134.1,129.5,128.6,127.4,122.1,121.3,110.1,62.5,48.6,41.5,40.4,21.7,13.9；高分辨質(zhì)譜m/z：計(jì)算值C24H23NNaO6+[M+Na+] 444.141 8,測(cè)量值444.141 7.

產(chǎn)物3ad 淡黃色固體；熔點(diǎn):137～138 ℃;IR(KBr)σ/cm-1:3 065,2 989,1 743,1 728,1 689,1 590,1 489,1 471,1 261,894,821,748,685,570;1H NMR(600 MHz,CDCl3)δ:7.71(dd,J=7.7,1.6 Hz,1H),7.45～7.30(m,5H),7.02(s,1H),6.91(d,J=7.6 Hz,1H),4.31(dd,J=16.4,9.3 Hz,4H),4.12(s,1H),3.27(d,J=23.5 Hz,3H),1.31(t,J=7.1 Hz,2H),1.28(t,J=7.1 Hz,2H),1.22(s,1H),1.08(s,1H);13C NMR(150 MHz,CDCl3)δ:192.2,171.4,165.0,164.6,163.3,144.6,137.1,133.1,132.4,130.9,130.6,128.8,127.2,127.0,122.7,122.2,108.2,62.6,62.5,48.6,44.2,42.6,26.8,13.9；高分辨質(zhì)譜m/z：計(jì)算值C24H22ClNNaO6+[M+Na+] 478.102 8,測(cè)量值478.102 8.

產(chǎn)物3ae 淡黃色固體；熔點(diǎn):130～133 ℃；IR(KBr)σ/cm-1:3 063,2 990,1 742,1 730,1 689,1 594,1 493,1 476,1 258,889,832,746,678,577;1H NMR(600 MHz,CDCl3)δ:8.21(s,1H),8.12(d,J=7.8 Hz,1H),7.55(d,J=1.1 Hz,1H),7.44(t,J=7.9 Hz,1H),7.38～7.28(m,3H),7.04(t,J=7.5 Hz,1H),6.92(d,J=7.8 Hz,1H),4.35(q,J=7.1 Hz,2H),4.12(dd,J=11.0,7.1 Hz,2H),3.96(s,1H),3.29(s,3H),1.36(t,J=7.1 Hz,3H),1.12(t,J=7.1 Hz,3H);13C NMR(150 MHz,CDCl3)δ:189.1,171.5,164.8,163.5,144.8,138.1,135.1,133.6,130.1,128.9,128.4,126.7,122.3,120.7,108.4,62.7,49.1,40.9,40.0,26.9,14.0,13.8；高分辨質(zhì)譜m/z：計(jì)算值C24H22ClNNaO6+[M+Na+] 478.102 8,測(cè)量值478.101 1.

產(chǎn)物3af 淡黃色固體；熔點(diǎn):129～131 ℃;IR(KBr)σ/cm-1:3 062,2 989,1 741,1 728,1 696,1 591,1 495,1 469,1 263,904,825,758,693,569;1H NMR(600 MHz,CDCl3)δ:8.16(d,J=8.6 Hz,2H),7.46(d,J=8.5 Hz,2H),7.36～7.29(m,2H),7.03(t,J=7.8 Hz,1H),6.92(d,J=7.7 Hz,1H),4.32(dd,J=15.3,8.3 Hz,3H),4.12(dd,J=7.1,4.3 Hz,2H),3.97(s,1H),3.29(s,3H),1.33(t,J=7.2 Hz,4H),1.13(t,J=7.1 Hz,3H);13C NMR(150 MHz,CDCl3)δ:189.1,171.5,165.0,163.5,144.7,140.2,135.0,130.5,129.9,129.1,128.8,126.8,122.2,120.7,108.4,62.6,48.9,41.0,40.1,26.9,13.9,13.8；高分辨質(zhì)譜m/z：計(jì)算值C24H22ClNNaO6+[M+Na+] 478.102 8,測(cè)量值478.101 3.

產(chǎn)物3ag 淡黃色固體；熔點(diǎn):159～160 ℃;IR(KBr)σ/cm-1:3 001,2 979,1 742,1 719,1 586,1 493,1 470,1 236,832,768,518;1H NMR(600 MHz,CDCl3)δ:8.08(d,J=8.3 Hz,2H),7.62(d,J=8.3 Hz,2H),7.32(dd,J=7.6,5.0 Hz,2H),7.03(t,J=7.7 Hz,1H),6.91(d,J=7.8 Hz,1H),4.37～4.26(m,2H),4.12(dd,J=7.1,4.4 Hz,2H),3.96(s,1H),3.29(s,3H),1.33(t,J=7.1 Hz,3H),1.13(t,J=7.1 Hz,3H);13C NMR(150 MHz,CDCl3)δ:189.3,171.5,165.0,163.5,144.7,135.4,132.1,129.9,128.9,126.8,122.2,120.7,108.4,62.6,48.9,41.0,40.0,26.9,13.9,13.8；高分辨質(zhì)譜m/z：計(jì)算值C24H22BrNNaO6+[M+Na+] 522.052 3,測(cè)量值522.052 3.

產(chǎn)物3ba 淡黃色固體；熔點(diǎn):161～163 ℃;IR(KBr)σ/cm-1:3 061,2 978,1 751,1 712,1 489,1 595,1 470,1 247,978;1H NMR(600 MHz,CDCl3)δ:8.20(d,J=7.4 Hz,2H),7.57(d,J=7.4 Hz,1H),7.47(t,J=7.8 Hz,2H),7.40(d,J=7.7 Hz,1H),7.36～7.29(m,4H),7.27(dd,J=11.0,6.7 Hz,1H),7.19(dd,J=11.3,4.2 Hz,1H),6.99(t,J=7.7 Hz,1H),6.79(d,J=7.9 Hz,1H),5.15(d,J=15.8 Hz,1H),4.82(d,J=15.8 Hz,1H),4.35(dd,J=10.7,7.2 Hz,1H),4.27(dd,J=10.7,7.2 Hz,1H),4.16～4.06(m,3H),1.29(t,J=7.2 Hz,3H),1.12(t,J=7.1 Hz,3H);13C NMR(150 MHz,CDCl3)δ:190.1,172.0,165.2,163.7,143.8,136.6,135.4,133.7,128.9,128.6,128.5,127.7,127.2,122.2,120.9,109.2,62.5,48.9,44.3,41.1,40.6,13.9,13.8；高分辨質(zhì)譜m/z：計(jì)算值C30H27NNaO6+[M+Na+] 520.173 1,測(cè)量值520.172 9.

產(chǎn)物3bb 淡黃色固體；熔點(diǎn):146～148 ℃;IR(KBr)σ/cm-1:3 060,2 981,1 725,1 684,1 577,1 489,1 455,1 252,1 268,833,753,697;1H NMR(600 MHz,CDCl3)δ:8.19(d,J=8.9 Hz,2H),7.46～7.41(m,1H),7.35(d,J=4.4 Hz,4H),7.29(s,1H),7.21(d,J=1.0 Hz,1H),7.03～6.94(m,3H),6.81(d,J=7.8 Hz,1H),5.18(d,J=15.8 Hz,1H),4.85(d,J=15.8 Hz,1H),4.38(dq,J=10.8,7.1 Hz,1H),4.33～4.26(m,1H),4.18(dd,J=7.1,4.0 Hz,2H),4.11(s,1H),3.89(d,J=4.4 Hz,3H),1.31(t,J=7.2 Hz,3H),1.18(dd,J=12.4,5.3 Hz,3H);13C NMR(150 MHz,CDCl3)δ:188.5,172.1,165.4,164.0,163.7,143.8,135.5,131.5,130.8,129.8,128.8,128.5,127.7,127.3,127.2,122.2,121.0,113.9,113.7,109.1,62.5,55.5,48.7,44.3,41.1,40.6,13.9；高分辨質(zhì)譜m/z：計(jì)算值C31H29NNaO7+[M+Na+] 550.183 6,測(cè)量值550.177 2.

產(chǎn)物3bc 淡黃色固體；熔點(diǎn):171～173 ℃;IR(KBr)σ/cm-1:3 069,2 981,1 735,1 708,1 690,1 598,1 490,1 221,906,804,746,688;1H NMR(600 MHz,CDCl3)δ:8.11(d,J=8.1 Hz,2H),7.43(d,J=7.8 Hz,1H),7.33(dd,J=34.7,6.3 Hz,7H),7.22(s,1H),7.01(s,1H),6.81(d,J=7.8 Hz,1H),5.18(d,J=15.8 Hz,1H),4.86(d,J=15.8 Hz,1H),4.42～4.26(m,2H),4.22～4.05(m,3H),2.43(s,3H),1.32(t,J=7.1 Hz,3H),1.18(t,J=7.2 Hz,3H);13C NMR(150 MHz,CDCl3)δ:189.7,172.0,165.2,163.7,144.7,143.8,135.5,134.2,129.5,129.2,128.8,128.6,127.7,127.4～127.1,122.2,121.0,109.1,62.5,48.8,44.3,41.1,40.7,21.8,13.9,13.8；高分辨質(zhì)譜m/z：計(jì)算值C31H29NNaO6+[M+Na+] 534.188 7,測(cè)量值534.188 8.

產(chǎn)物3bd 淡黃色固體；熔點(diǎn):171～173 ℃;IR(KBr)σ/cm-1:3 062,2 989,1 741,1 728,1 696,1 591,1 495,1 469,1 263,904,825,758,693,569;1H NMR(600 MHz,CDCl3)δ:8.18(d,J=8.6 Hz,2H),7.49～7.41(m,2H),7.36(d,J=7.8 Hz,1H),7.34～7.30(m,4H),7.28(d,J=5.2 Hz,1H),7.20(dd,J=7.7,1.1 Hz,1H),7.02～6.96(m,1H),6.80(d,J=7.8 Hz,1H),5.17(d,J=15.8 Hz,1H),4.80(d,J=15.8 Hz,1H),4.35(d,J=7.2 Hz,1H),4.27(d,J=7.2 Hz,1H),4.16～4.04(m,2H),4.01(s,1H),1.29(t,J=7.2 Hz,3H),1.12(t,J=7.1 Hz,3H);13C NMR(150 MHz,CDCl3)δ:188.9,171.8,165.2,163.6,143.9,140.2,135.4,135.0,130.5,129.9,129.1,128.9～128.7,127.7,127.3,127.1,122.3,120.8,109.3,62.6,49.1,44.3,41.0,40.3,13.9,13.8；高分辨質(zhì)譜m/z：計(jì)算值C30H26ClNNaO6+[M+Na+] 554.134 1,測(cè)量值554.132 5.

產(chǎn)物3be 淡黃色固體；熔點(diǎn):154～155 ℃;IR(KBr)σ/cm-1:3 001,2 979,1 742,1 719,1 586,1 493,1 470,1 236,832,768,518;1H NMR(600 MHz,CDCl3)δ:8.10(d,J=8.5 Hz,2H),7.62(d,J=8.6 Hz,2H),7.36(d,J=7.7 Hz,1H),7.32(d,J=4.3 Hz,4H),7.26(dd,J=11.7,6.8 Hz,1H),7.20(t,J=7.8 Hz,1H),6.99(t,J=7.7 Hz,1H),6.80(d,J=7.9 Hz,1H),5.16(d,J=15.8 Hz,1H),4.79(d,J=15.8 Hz,1H),4.36(dd,J=10.8,7.2 Hz,1H),4.26(dd,J=10.7,7.2 Hz,1H),4.17～4.04(m,2H),4.01(s,1H),1.28(t,J=7.2 Hz,3H),1.12(t,J=7.1 Hz,3H);13C NMR(150 MHz,CDCl3)δ:189.2,171.8,165.2,163.6,143.9,135.4,132.1,130.0,129.0,128.8,127.8,127.2,127.0,122.3,120.8,109.3,62.7,49.1,44.3,41.0,40.3,13.9,13.8；高分辨質(zhì)譜m/z：計(jì)算值C30H26BrNNaO6+[M+Na+] 598.094 4,測(cè)量值598.094 4.

產(chǎn)物3ca 淡黃色固體；熔點(diǎn):69～73 ℃；IR(KBr)σ/cm-1:3 372,3 070,2 981,1 736,1 695,1 597,1 490,1 473,1 221,908,807,748,689;1H NMR(400 MHz,CDCl3)δ:8.46(s,1H),8.06(d,J=8.2 Hz,2H),7.36(d,J=7.8 Hz,1H),7.28(t,J=4.0 Hz,4H),6.98(dd,J=28.9,7.8 Hz,2H),4.33(dd,J=11.5,7.1 Hz,2H),4.18(dd,J=11.2,4.8 Hz,2H),4.06(s,1H),2.42(s,3H),1.33(t,J=7.1 Hz,3H),1.18(t,J=7.1 Hz,3H);13C NMR(150 MHz,CDCl3)δ:189.7,173.8,165.2,163.5,144.7,141.7,134.1,129.5,128.6,127.4,122.1,121.3,110.1,62.5,48.6,41.5,40.4,21.7,13.9；高分辨質(zhì)譜m/z：計(jì)算值C24H23NNaO6+[M+Na+] 444.141 8,測(cè)量值444.141 7.

產(chǎn)物3cb 淡黃色固體；熔點(diǎn):137～139 ℃;IR(KBr)σ/cm-1:3 385,3 062,2 989,1 741,1 721,1 695,1 589,1 490,1 471,1 267,903,884,767,752;1H NMR(600 MHz,CDCl3)δ:8.54(s,1H),8.21(s,1H),8.12(d,J=7.8 Hz,1H),7.58～7.54(m,1H),7.44(t,J=7.9 Hz,1H),7.28(q,J=8.1 Hz,2H),7.01(s,1H),6.94(d,J=7.6 Hz,1H),4.33(dd,J=15.5,7.2 Hz,2H),4.13(dd,J=9.7,5.6 Hz,2H),3.95(s,1H),1.26(dd,J=13.3,7.0 Hz,3H),1.12(q,J=7.3 Hz,3H);13C NMR(150 MHz,CDCl3)δ:188.9,172.7 164.9,163.4,141.9,138.1,135.1,133.6,130.2,128.9,128.5,126.6,122.2,121.1,110.3,62.7,49.1,41.3,40.0,13.9,13.8；高分辨質(zhì)譜m/z：計(jì)算值C23H20ClNNaO6+[M+Na+] 464.087 1,測(cè)量值464.087 4.

產(chǎn)物3cc 淡黃色固體；熔點(diǎn):138～139 ℃;IR(KBr)σ/cm-1:3 385,3 062,2 989,1 741,1 721,1 695,1 589,1 490,1 471,1 267,903,884,767,752;1H NMR(600 MHz,CDCl3)δ:8.54(s,1H),8.21(s,1H),8.12(d,J=7.8 Hz,1H),7.58～7.54(m,1H),7.44(t,J=7.9 Hz,1H),7.28(q,J=8.1 Hz,2H),7.01(s,1H),6.94(d,J=7.6 Hz,1H),4.33(dd,J=15.5,7.2 Hz,2H),4.13(dd,J=9.7,5.6 Hz,2H),3.95(s,1H),1.26(dd,J=13.3,7.0 Hz,3H),1.12(q,J=7.3 Hz,3H);13C NMR(150 MHz,CDCl3)δ:188.9,172.7,164.9,163.4,141.9,138.1,135.1,133.6,130.2,128.9,128.5,126.6,122.2,121.1,110.3,62.7,49.1,41.3,40.0,13.9,13.8；高分辨質(zhì)譜m/z：計(jì)算值C23H20ClNNaO6+[M+Na+] 464.087 1,測(cè)量值464.087 4.

3 結(jié) 論

本文首次以各種不同取代基的靛紅衍生物烯酮為原料，在手性伯胺Ⅳ/碳酸銫共同催化下，以二氯甲烷為溶劑，常溫下分別與溴代丙二酸二乙酯發(fā)生麥克爾/烷基化串聯(lián)反應(yīng)，以高達(dá)97%的產(chǎn)率及高達(dá)99∶1的非對(duì)映選擇性高效地合成了螺靛紅環(huán)丙烷衍生物.該新型的螺環(huán)化合物具有潛在的生物、生理活性.此外，這些化合物具有2個(gè)季碳中心，并且同時(shí)具有多個(gè)可以官能團(tuán)化的羰基，為進(jìn)一步合成其他活性物質(zhì)提供了很好的骨架單元.

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(責(zé)任編輯 薛 榮)

Efficient synthesis of spirooxindole cyclopropanes via a domino Michael/alkylation catalyzed by chiral primary amine

XIE Jianwu， YU Chaobo, XU Meilan

(CollegeofChemistryandLifeSciences,ZhejiangNormalUniversity,Jinhua321004,China)

In order to synthesize compounds containing both cyclopropane and 2-oxoindoles units, an efficient, mild, and convenient method for the preparation of spirooxindole cyclopropanes via a domino Michael/alkylation catalyzed by chiral primary amine was developed. A series of spirooxindole cyclopropanes were obtained in 47%～97% yields when the domino reactions were carried out in the optimized conditions (catalyzed by chiral primary amine/Cs2CO3using dichloromethane as solvent and stirred for 48 hours).

Michael addition; alkylation′s; cyclopropanes; isatin

10.16218/j.issn.1001-5051.2017.01.008

2016-03-14；

2016-05-26

國(guó)家自然科學(xué)基金資助項(xiàng)目(21272214)

謝建武(1978-)，男，廣西博白人，教授，博士.研究方向:有機(jī)合成.

TQ453.2

A

1001-5051(2017)01-0051-07