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(hù)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?yàn)楦叨鹊脑咏?jīng)濟(jì)性而備受有機(jī)化學(xué)家的關(guān)注[1]。 近年來(lái)隨著金屬催化[2]和有機(jī)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(jìn)展。總結(jié)目前的研究工作我們發(fā)現(xiàn)，當(dāng)前報(bào)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(duì)較少。α,β-不飽和羧酸衍生物[7]因?yàn)檩^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(shí)，需要在當(dāng)量的催化劑下經(jīng)過(guò)長(zhǎng)時(shí)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(qiáng)吸電子三氟甲基的α,β-不飽和?；吝虿拍軌蛴行c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(wú)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(guò)簡(jiǎn)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(yùn)用于Manich反應(yīng)，但是其作為給體的Michael加成反應(yīng)還有待進(jìn)一步開(kāi)發(fā)[13-19]。我們一直致力于發(fā)展α,β-不飽和?；吝騾⑴c的Michael加成反應(yīng)，[20]在本論文中，我們進(jìn)一步拓展給體類型，成功發(fā)展了α,β-不飽和?；吝蚺cα-硝基乙酸酯的Michael加成反應(yīng)；同時(shí)我們還發(fā)現(xiàn)，得到的加成產(chǎn)物經(jīng)過(guò)簡(jiǎn)單處理，即轉(zhuǎn)化為相應(yīng)的功能分子。

1 實(shí)驗(yàn)部分

1.1 藥品及儀器

苯和甲醇均購(gòu)至成都科龍?jiān)噭┕尽?,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(gòu)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(gòu)自阿拉丁試劑有限公司。α,β-不飽和羧酸購(gòu)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(biāo))，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?；吝虻暮铣蒣21]

α,β-不飽和酰基吡唑的合成反應(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(guò)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(guò)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?；吝虻腗ichael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(jiàn)表1。

表1 α-硝基乙酸酯與α,β-不飽和?；吝虻腗ichael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(jìn)行，在三乙胺的催化下在較短的時(shí)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-不飽和酰基吡唑都能順利參與加成反應(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(zhǎng)的反應(yīng)時(shí)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(guò)1H-NMR、13C-NMR和HRMS驗(yàn)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(duì)稱合成方法，期待能夠高對(duì)映選擇性地構(gòu)建一系列γ-取代的羧酸衍生物。

[1] Sibi MP,Manyem S. Enantioselective conjugate additions[J].Tetrahedron,2000,56(41):8033-8061.

[2] Christoffers J,Koripelly G,Rosiak A,R?ssle M.Recent advances in metal-catalyzed asymmetric conjugate additions[J].Synthesis,2007(9):1279-1300.

[3] Almasi D, Alonso DA,Najera C.Organocatalytic asymmetric conjugate additions[J].Tetrahedron:Asymmetry,2007,18(3):299-365.

[4] Xu L W,Luo J,Lu Y.Asymmetric catalysis with chiral primary amine-based organocatalysts[J].Chemical Communications,2009(14):1807-1821.

[5] Berner O M,Tedeschi L,Enders D.Asymmetric michael additions to nitroalkenes[J].European Journal of Organic Chemistry,2002,2002(12): 1877-1894.

[6] Desimoni G,Faita G,Quadrelli P.Substituted (E)-2-Oxo-3-butenoates:Reagents for every enantioselectively-catalyzed reaction[J].Chemical Reviews,2013,113(8): 5924-5988.

[7] Desimoni G,Faita G,Quadrelli P.Enantioselective catalytic reactions with N-acyliden penta-atomic aza-heterocycles. heterocycles as masked bricks to build chiral scaffolds[J].Chemical Reviews,2015,115(18):9922-9980.

[8] Sibi M P,Itoh K.Organocatalysis in conjugate amine additions.Synthesis of β-amino acid derivatives[J].Journal of the American Chemical Society,2007,129(26): 8064-8065.

[9] Dong X Q,Fang X,Tao H Y,et al.Highly efficient catalytic asymmetric sulfa‐michael addition of thiols to trans‐4, 4, 4‐trifluorocrotonoylpyrazole[J].Advanced Synthesis & Catalysis,2012,354(6):1141-1147.

[10] Singh A,Yoder R A,Shen B,et al.Chiral proton catalysis:enantioselective br?nsted acid catalyzed additions of nitroacetic acid derivatives as glycine equivalents[J]. Journal of the American Chemical Society,2007,129(12):3466-3467.

[11] Singh A,Johnston J N.A diastereo- and enantioselective synthesis of α-substituted syn-α,β-diamino acids[J].Journal of the American Chemical Society,2008,130(18):5866-5867.

[12] Shen B,Johnston J N.A formal enantioselective acetate mannich reaction: the nitro functional group as a traceless agent for activation and enantiocontrol in the synthesis of β-amino acids[J].Organic Letters,2008,10(20):4397-4400.

[13] Lu R-j,Wei W-t,Wang J-j,et al.Organocatalytic conjugate addition of α-nitroacetates to β,γ-unsaturated α-keto esters and subsequent decarboxylation:synthesis of optically active δ-nitro-α-keto esters[J].Tetrahedron,2012,68(46):9397-9404.

[14] Wang Q,Gong J,Liu Y,et al.Chiral bifunctional squaramide catalyzed asymmetric Michael addition of ethyl α-nitroacetate to β,γ-unsaturated α-ketoesters[J].Tetrahedron,2014,70(43):8168-8173.

[15] Liu R l,Yan Y y,Zhang T,et al.A practical synthesis of optically active δ-nitro-α-ketoesters and 4-cyclohexyl-proline catalyzed by chiral squamides[J].Tetrahedron: Asymmetry,2015,26(24):1416-1422.

[16] Shirakawa S,Terao S J,He R,et al.Diastereo- and enantioselective conjugate addition of [small alpha]-substituted nitroacetates to maleimides under base-free neutral phase-transfer conditions[J].Chemical Communications,2011,47(38):10557-10559.

[17] Liu R l，Tang X Z,Zhang X J,et al.Organocatalytic asymmetric conjugate addition of t-butyl nitroacetate to o-quinone methides:synthesis of optically active [small alpha]-nitro-[small beta],[small beta]-diaryl-propionates[J].RSC Advances,2017,7(11):6660-6663.

[18] Han M Y, Zhang Y,Wang H Z,et al.Organocatalytic michael addition of nitro esters to α,β-unsaturated aldehydes: towards the enantioselective synthesis of trans-3-substituted proline derivatives[J].Advanced Synthesis & Catalysis,2012,354(14-15):2635-2640.

[19] Liu C,Lu Y.Primary amine/(+)-CSA salt-promoted organocatalytic conjugate addition of nitro esters to enones[J].Organic Letters,2010,12(10):2278-2281.

[20] Zheng Y,Yao Y,Ye L,et al.Highly enantioselective michael addition of malononitrile to α,β-unsaturated pyrazolamides catalyzed by a bifunctional thiourea[J].Tetrahedron,2016,72(7):973-978.

[21] Zhang J,Liu X,Wang R.Magnesium complexes as highly effective catalysts for conjugate cyanation of α, β‐unsaturated amides and ketones[J].Chemistry- A European Journal,2014,20(17):4911-4915.

[22] Yao Q,Wang Z,Zhang Y,et al.N, N'-Dioxide/gadolinium (III)-catalyzed asymmetric conjugate addition of nitroalkanes to alpha, beta-unsaturated pyrazoleamides[J]. Journal of Organic Chemistry,2015,80:5704-5712.