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        三乙胺催化的α-硝基乙酸酯與α,β-不飽和?;吝虻腗ichael加成反應(yīng)

        2018-05-09 07:50:02劉瑩瑩李雪鋒
        山東化工 2018年8期

        劉瑩瑩,何 謙,陳 峰,李雪鋒

        (西南民族大學(xué)化學(xué)與環(huán)境保護工程學(xué)院,四川 成都 610041)

        Michael加成反應(yīng)是構(gòu)建碳碳鍵的重要方法之一,因為高度的原子經(jīng)濟性而備受有機化學(xué)家的關(guān)注[1]。 近年來隨著金屬催化[2]和有機催化[3]的蓬勃發(fā)展,Michael加成反應(yīng)也取得了一系列重要進展??偨Y(jié)目前的研究工作我們發(fā)現(xiàn),當(dāng)前報導(dǎo)的Michael加成反應(yīng)主要以α,β-不飽和醛/酮[4]、α,β-不飽和硝基烯烴[5]以及β,γ-不飽和α-酮酸酯[6]作為受體,其它受體參與的反應(yīng)相對較少。α,β-不飽和羧酸衍生物[7]因為較低的反應(yīng)活性而不能有效地參與Michael加成反應(yīng),其中α,β-不飽和酰基吡唑在發(fā)生氮雜Michael加成反應(yīng)時,需要在當(dāng)量的催化劑下經(jīng)過長時間反應(yīng),才能以滿意的產(chǎn)率轉(zhuǎn)化為加成產(chǎn)物[8];此外,只有雙鍵末端含強吸電子三氟甲基的α,β-不飽和酰基吡唑才能夠有效與苯硫酚發(fā)生加成反應(yīng)[9]。因此,發(fā)展α,β-不飽和羧酸衍生物參與的Michael加成反應(yīng),無疑具有一定的挑戰(zhàn)性。

        α-硝基乙酸酯是一種高活性的親核試劑,其加成產(chǎn)物經(jīng)過簡單的還原-水解處理即轉(zhuǎn)化為取代的α-氨基酸,因此在合成領(lǐng)域受到廣泛關(guān)注[10-12]。 盡管α-硝基乙酸酯已經(jīng)被廣泛運用于Manich反應(yīng),但是其作為給體的Michael加成反應(yīng)還有待進一步開發(fā)[13-19]。我們一直致力于發(fā)展α,β-不飽和酰基吡唑參與的Michael加成反應(yīng),[20]在本論文中,我們進一步拓展給體類型,成功發(fā)展了α,β-不飽和酰基吡唑與α-硝基乙酸酯的Michael加成反應(yīng);同時我們還發(fā)現(xiàn),得到的加成產(chǎn)物經(jīng)過簡單處理,即轉(zhuǎn)化為相應(yīng)的功能分子。

        1 實驗部分

        1.1 藥品及儀器

        苯和甲醇均購至成都科龍試劑公司。3,5-二甲基吡唑、乙腈、三乙胺(TEA)和1,8-二氮雜雙環(huán)[5.4.0]十一碳-7-烯(DBU)購自上海泰坦科技股份有限公司。二環(huán)己基二亞胺(DCC)、4-二甲氨基吡啶(DMAP)、α-硝基乙酸乙酯、α-硝基乙酸甲酯、偶氮二異丁腈(AIBN)和三丁基氫化錫購自阿拉丁試劑有限公司。α,β-不飽和羧酸購自天津希恩思生化科技有限公司。所有溶劑和α-硝基乙酸酯未經(jīng)純化直接使用。所有試劑均為分析純。

        Varian 400 MHz型核磁共振儀(CDCl3為溶劑,TMS為內(nèi)標),Bruker Daltonics LCQDECA型離子阱高分辨質(zhì)譜儀。

        1.2 合成

        1.2.1 α,β-不飽和酰基吡唑的合成[21]

        α,β-不飽和?;吝虻暮铣煞磻?yīng)式:

        在100 mL圓底瓶中加入肉桂酸(1.1g, 10 mmol)和3,5-二甲基-4-氯吡唑(1.3g, 10 mmol),將混合物溶解于二氯甲烷(30 mL)后置于冰浴中冷卻。然后向溶液中加入二環(huán)己基二亞胺(DCC,2.25g, 12 mmol),接著滴加4-二甲氨基吡啶(DMAP,0.123g,1 mmol)的二氯甲烷溶液(10 mL)。滴加完畢后,反應(yīng)混合物繼續(xù)在冰浴中攪拌30min,然后移走冰浴逐漸升至室溫,并繼續(xù)攪拌24h。待α,β-不飽和羧酸完全反應(yīng)后,蒸除大部分溶劑,然后加入50 mL乙醚。過濾取濾液,濃縮后經(jīng)柱層析得到白色粉末1.55g, 產(chǎn)率78%。1H NMR(400 MHz,CDCl3) δ(ppm)7.95~7.87(m,2H),7.69~7.67(m,2H),7.43~7.41(m, 3H),2.63(s,3H),2.31(s,3H);13C NMR(100 MHz,CDCl3)δ(ppm)164.9,149.2,146.8,139.5,134.6,130.8,128.9,128.7,116.8,114.8,12.6,11.8。

        化合物1b-1i按照類似方法合成。

        1b,黃色晶體,產(chǎn)率60%;1H NMR(400 MHz,CDCl3)δ (ppm) 7.88~7.77 (m,2H),7.67~7.62(m,2H),7.12~7.07(m,2H),2.60(s,3H),2.27(s,3H)。

        1c,黃色晶體,產(chǎn)率80%;1H NMR(400 MHz, CDCl3)δ(ppm)8.35(d,J=15.6 Hz,1H ),7.90(d,J=16.0 Hz,1H ),7.85~7.83(m,1H),7.45~7.43(m,1H),7.34~7.30(m,2H),2.63 (s,3H),2.30(s,3H)。

        1d,黃色晶體,產(chǎn)率77%;1H NMR(400 MHz, CDCl3)δ(ppm)7.84~7.83(m,2H),7.59~7.57(m,2H),7.38~7.35(m,2H),2.60(s,3H),2.28(s, 3H)。

        1e,黃色晶體,產(chǎn)率75%;1H NMR(400 MHz,CDCl3)δ(ppm)7.89(d,J=15.6 Hz,1H ),7.82(d,J=16.0 Hz,1H ),7.56~7.26(m,4H),2.62(s,3H),2.30(s, 3H)。

        1f,黃色晶體,產(chǎn)率83%;1H NMR(400 MHz, CDCl3)δ(ppm)7.84~7.82(m,2H ),7.54~7.52(m,2H),7.19~7.17(m,2H),2.58(s,3H),2.36(s,3H)2.27(s,3H)。

        1g,黃色晶體,產(chǎn)率65%;1H NMR(400 MHz,CDCl3)δ(ppm)7.86(d,J=16.0 Hz,1H ),7.74(d,J=15.6 Hz,1H ),7.63~7.60(m,2H),6.93~6.89(m,2H),3.84(s,3H),2.61(s,3H), 2.29(s,3H)。

        1h,黃色晶體,產(chǎn)率62%;1H NMR(400 MHz,CDCl3)δ(ppm)7.74(d,J=16.0 Hz,1H ),7.64(d,J=15.6 Hz,1H ),7.541~7.539(m,1H),6.74(d,J=3.2 Hz,1H)6.51~6.50(m,1H), 2.62(s,3H)2.30(s,3H)。

        1i,黃色晶體,產(chǎn)率60%;1H NMR(400 MHz,CDCl3)δ(ppm)8.75(d,J=15.6 Hz,1H ),8.24(d,J=8.8 Hz,1H),7.96(d,J=22.8 Hz,1H),7.95(s,1H),7.88(d,J=8.4 Hz,1H),7.84(d,J=8.4 Hz,1H)7.56(t,J=7.6 Hz,1H),7.52~7.45(m,2H),2.62(s,3H),2.28(s,3H)。

        1.2.2 α,β-不飽和?;吝蚺cα-硝基乙酸酯的Michael加成反應(yīng)

        化合物3ab-3ai, 3ba按照類似方法合成。

        1.2.3 加成產(chǎn)物的醇解[22]

        將3aa (39.3 mg, 0.1 mol)溶于甲醇(0.2 mL)中,然后加入DBU(10 μL,0.67 mol),并在30 ℃下攪拌過夜。薄層色譜顯示3aa完全轉(zhuǎn)化后,減壓蒸除溶劑,殘余物經(jīng)乙酸乙酯/石油醚體系柱層析后得到白色固體27.0 mg, 產(chǎn)率96%, dr值為1∶1。1H NMR(400 MHz,CDCl3)δ(ppm)7.31~7.26(m,10H),5.55(d,J=10.0 Hz,1H), 5.47(d,J=8.8 Hz,1H),4.23~4.20(m,2H),3.84(s,3H),3.61(s,3H),3.59(s,3H),3.58(s,3H),3.00~2.81(m,4H);13C NMR(100 MHz,CDCl3)δ(ppm)170.8,170.7,163.8,163.4,137.0,136.1,129.0,128.33,128.29,128.1,127.9,91.0,90.9,53.7,53.5,51.95,51.92,42.6,42.4,36.7, 36.4;ESI-HRMS:calcd.for C13H16NO6(M+H)+282.0972,found 282.0975。

        2 結(jié)果與討論

        α-硝基乙酸酯與α,β-不飽和酰基吡唑的Michael加成反應(yīng):

        α-硝基乙酸酯與α,β-不飽和?;吝虻腗ichael加成反應(yīng)條件及收率見表1。

        表1 α-硝基乙酸酯與α,β-不飽和酰基吡唑的Michael加成反應(yīng)Tab.1 Michael addition of α,β-unsaturated pyrazolamides and α-nitroacetate.

        雖然早期的研究表明,α,β-不飽和酰基吡唑在Michael加成反應(yīng)中活性較低;然而我們發(fā)現(xiàn),如果選用活性較高的α-硝基乙酸酯作為給體,相應(yīng)的Michael加成能夠順利進行,在三乙胺的催化下在較短的時間內(nèi)以中等及以上產(chǎn)率(50%~88%)得到加成產(chǎn)物。反應(yīng)表現(xiàn)出較好的底物適應(yīng)性,各種電子性質(zhì)的α,β-不飽和?;吝蚨寄茼樌麉⑴c加成反應(yīng),只是富電子的?;吝?f-1g活性比貧電子的?;吝?b-1e活性略低,相應(yīng)的共軛加成反應(yīng)需要更長的反應(yīng)時間(entries 6 and 7 vs entries 2-5)。含有雜芳基的化合物1h也能作為受體參與加成反應(yīng),只是呋喃環(huán)較大的電子云密度導(dǎo)致了較低的反應(yīng)活性(entry 8)。含有萘環(huán)的?;吝?i也是合適的受體,反應(yīng)較低的轉(zhuǎn)化率可能是萘環(huán)的位阻所致(entry 9)。除α-硝基乙酸乙酯2a,α-硝基乙酸甲酯2b也能夠順利參與反應(yīng)(entry 10)。

        加成反應(yīng)得到的產(chǎn)物是有用的合成子,能夠轉(zhuǎn)化為其它的功能分子。在DBU的作用下,化合物3aa順利發(fā)生醇解反應(yīng),以較高的產(chǎn)率轉(zhuǎn)化為γ-位官能化的酯4(eq 3)。

        3 結(jié)論

        綜上所述,我們成功地發(fā)展了α,β-不飽和酰基吡唑與α-硝基乙酸酯的Michael加成反應(yīng)。反應(yīng)表現(xiàn)出較好的底物適應(yīng)性,一系列不同類型的α,β-不飽和?;吝蚨寄軌蝽樌cα-硝基乙酸酯發(fā)生共軛加成。產(chǎn)物的結(jié)構(gòu)都經(jīng)過1H-NMR、13C-NMR和HRMS驗證。得到的產(chǎn)物在溫和的條件下即轉(zhuǎn)化為有用的功能分子。目前我們課題組正在嘗試發(fā)展相應(yīng)的不對稱合成方法,期待能夠高對映選擇性地構(gòu)建一系列γ-取代的羧酸衍生物。

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