4’-三氟甲基-3,2’-吡咯烷基雙螺環(huán)氧化吲哚化合物的合成與表征

朱文岐，鄧曉怡，魏江存，朱文潤(rùn)

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4’-三氟甲基-3,2’-吡咯烷基雙螺環(huán)氧化吲哚化合物的合成與表征

朱文岐1，鄧曉怡2，魏江存3，*朱文潤(rùn)3

（1.深圳市美普達(dá)環(huán)保設(shè)備有限公司，廣東，深圳 518122; 2.廣東藥科大學(xué)藥學(xué)院，廣東，廣州 510006; 3.廣西中醫(yī)藥大學(xué)藥學(xué)院，廣西，南寧 530200）

對(duì)具有高生物活性的4’-三氟甲基-3,2’-吡咯烷基雙螺環(huán)氧化吲哚及其衍生物進(jìn)行了探索合成。在有機(jī)小分子堿三乙胺催化作用下，由3-異硫氰基氧化吲哚與3-三氟亞乙基羥吲哚在二氯甲烷（DCM）溶劑中于室溫下發(fā)生3+2環(huán)合加成反應(yīng)，高產(chǎn)率(85%~96%)獲得4’-三氟甲基-3,2’-吡咯烷基雙螺環(huán)氧化吲哚。通過(guò)核磁共振氫譜和碳譜、高分辨質(zhì)譜等手段對(duì)已合成的產(chǎn)物進(jìn)行表征。這一合成方法具有簡(jiǎn)單，高效，環(huán)保的特點(diǎn)。

3,2’-吡咯烷基雙螺環(huán)氧化吲哚；3+2環(huán)合加成；生物活性；氟化學(xué)

螺環(huán)氧吲哚骨架廣泛存在于天然產(chǎn)物和生物活性相關(guān)化合物中[1-8]。在各種螺環(huán)核心中，吡咯烷基螺環(huán)氧吲哚由于其具有許多重要的生物學(xué)性質(zhì)而成為最具吸引力的合成靶標(biāo)[9-13,16-20]。

Scheme 1 具有生物活性的3,2'-吡咯烷基雙螺環(huán)吲哚類(lèi)化合物

此外，3,2'-吡咯烷基-雙螺環(huán)吲哚類(lèi)化合物已被證明具有很好的生物活性，如抗腫瘤、抗菌和抗結(jié)核活性(Scheme1)[21]。然而，與構(gòu)建3,3'-吡咯烷基螺環(huán)氧吲哚對(duì)映選擇性合成的大量報(bào)道相比，吡咯烷基螺環(huán)氧吲哚的研究相對(duì)較少，特別是3,2'-吡咯烷基雙螺環(huán)吲哚的合成相當(dāng)少[22-23]。因此，如何直接制備3,2'-吡咯烷基雙螺環(huán)吲哚的新的合成方法，仍然是一個(gè)迫切的且重要的目標(biāo)。

鑒于 CF3的引入和吡咯烷基雙螺氧基吲哚骨架的意義，在這里我們開(kāi)發(fā)了一種新的、高效率的CF3基團(tuán)引入到3,2'-吡咯烷基雙螺代吲哚結(jié)構(gòu)。邁克爾/環(huán)化級(jí)聯(lián)反應(yīng)已經(jīng)成為快速構(gòu)建光學(xué)活性吡咯烷基化合物的有力工具。據(jù)我們所知，迄今為止還沒(méi)有關(guān)于在吡咯烷的C3位置中合成這種CF3的報(bào)道。此外，3-異硫氰基氧化吲哚已經(jīng)被證明是高度穩(wěn)定且多用途的邁克爾供體[22,24-30]。同時(shí)，迄今為止，僅有兩例3-三氟亞乙基羥吲哚被用作Friedel-Crafts 烷基化/內(nèi)酯化反應(yīng)[14-15]和Diels-Alder環(huán)加成反應(yīng)[31]。最近，我們開(kāi)發(fā)了一種新型的靛紅衍生的含CF3的偶氮甲堿葉立德與亞甲基吲哚啉酮之間的1,3-偶極環(huán)加成反應(yīng)，從而得到3,3'-吡咯烷基-二吡咯并吲 哚[12]。我們?cè)O(shè)想通過(guò)3-異硫氰基羥吲哚1與靛紅衍生的3-三氟亞乙基羥吲哚2之間的Michael/環(huán)化級(jí)聯(lián)反應(yīng)可以構(gòu)建含CF3的二螺氧吲哚骨架3。

本研究嘗試?yán)?3-異硫氰基氧化吲哚和靛紅衍生的3-三氟亞乙基羥吲哚進(jìn)行3+2環(huán)合加成合成具有高生物活性的3,2'-吡咯烷基-雙螺環(huán)吲哚及其衍生物同時(shí)將CF3基團(tuán)引入其中。采用環(huán)保的有機(jī)小分子堿三乙胺作為催化劑，溫和的反應(yīng)條件，快速的反應(yīng)時(shí)間（5 min）收獲了高達(dá)85%~96%的產(chǎn)率(Scheme2)。同時(shí)合成了未見(jiàn)報(bào)道的化合物5個(gè)。

Scheme 2 反應(yīng)路線(xiàn)設(shè)計(jì)

1 實(shí)驗(yàn)部分

1.1 試劑及儀器

二氯甲烷（無(wú)水處理）、甲苯、四氫呋喃（無(wú)水處理）、三乙胺、靛紅、碘甲烷、鹽酸羥胺、對(duì)甲苯磺酸一水合物、氰化鈉、吲哚啉-2-酮、-BuOK、DMAP等為商業(yè)購(gòu)買(mǎi)，均為分析純。

EYELA N-1001DW 旋轉(zhuǎn)蒸發(fā)儀、2X2S-4真空泵、Bruker AVANCE III 400 MHz 型核磁共振儀、ThermoMAT 95XP 高分辨質(zhì)譜儀、EYELA PSL-1400 磁力攪拌低溫恒溫槽。核磁共振測(cè)試溶劑CDCl3,內(nèi)標(biāo)TMS。

1.2 化合物3的合成

1.2.1 化合物3a-3e的合成

分別稱(chēng)取3-異硫氰基氧化吲哚(1a)(1 mmol，0.204 g)和3-三氟亞乙基羥吲哚(1.1 mmol，0.250 g)于25 mL圓底燒瓶中，加入二氯甲烷（無(wú)水處理）5 mL 溶解后滴加10 mol%（0.1 mmol，0.010 g）的三乙胺。室溫下反應(yīng)5 min結(jié)束，薄層色譜監(jiān)測(cè)反應(yīng)進(jìn)程，展開(kāi)劑為石油醚（沸點(diǎn)60~90 ℃）：乙酸乙酯= 2:1。反應(yīng)結(jié)束后直接在反應(yīng)液中加入適量柱色譜硅膠，旋干，干法上柱，梯度洗脫，以石油醚：乙酸乙酯= 5:1和3:1為洗脫劑，得產(chǎn)物3a。

同上述反應(yīng)步驟，得產(chǎn)物3b-3e。

3a：產(chǎn)率90%，白色固體，mp = 167.6~168.9 ℃。1H NMR (400 MHz, CDCl3) δ 8.35 (d,= 7.7 Hz, 1H), 8.31 (s, 1H), 7.93 (d,= 8.2 Hz, 1H), 7.64 (d,= 7.4 Hz, 1H), 7.42 (q,= 7.8 Hz, 2H), 7.29-7.23 (m, 1H), 7.19 (t,= 7.6 Hz, 1H), 6.90 (d,= 7.8 Hz, 1H), 4.48 (q,= 9.1 Hz, 1H), 3.26 (s, 3H), 1.65 (s, 9H);13C NMR (100 MHz, CDCl3) δ 200.9, 173.3, 171.9, 148.6, 143.3, 140.8, 131.9, 130.3, 127.9, 126.0, 125.4, 124.8, 124.5, 124.4, 123.2 (q,J= 279.8 Hz), 115.2, 109.3, 85.4, 69.1, 68.0, 58.5 (q,J= 28.8 Hz), 28.2, 27.3;19F NMR (376 MHz, CDCl3) δ -62.84.HRMS (ESI):[M+Na]+calcd. for [C25H22F3N3NaO4S]+:540.1175, found:540.1172.

3b：產(chǎn)率96%，白色固體，Mp.176.5~177.9℃。1H NMR (400 MHz, CDCl3) δ 8.34 (d,= 7.7 Hz, 1H), 8.29 (s, 1H), 7.93 (d,= 8.2 Hz, 1H), 7.45 (s, 1H), 7.41 (t,= 7.9 Hz, 1H), 7.25 – 7.18 (m, 2H), 6.78 (d,= 7.9 Hz, 1H), 4.47 (q,= 9.1 Hz, 1H), 3.24 (s, 3H), 2.34 (s, 3H), 1.66 (s, 9H);13C NMR (100 MHz, CDCl3) δ 200.9, 173.4, 171.9, 148.6, 140.9, 140.8, 134.5, 132.1, 130.2, 128.0, 126.0, 125.3, 125.1, 124.8, 123.2 (q,J= 279.2 Hz), 115.2, 109.1, 85.4, 69.24, 68.0, 58.5 (q,J= 28.6 Hz), 28.2, 27.3, 21.1;19F NMR (376 MHz, CDCl3) δ -62.80. HRMS (ESI):[M+Na]+calcd. for [C26H24F3N3NaO4S]+: 554.1332, found: 554.1330.

3c：產(chǎn)率85%，白色固體，Mp.178.6~180.2℃。1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.32 (d,= 7.7 Hz, 1H), 7.93 (d,= 8.2 Hz, 1H), 7.42 (dd,= 11.6, 4.5 Hz, 2H), 7.26 (t,= 7.6 Hz, 1H), 7.14 (td,= 8.6, 2.3 Hz, 1H), 6.83 (dd,= 8.5, 3.8 Hz, 1H), 4.42 (q,= 9.1 Hz, 1H), 3.24 (s, 3H), 1.65 (s, 9H);13C NMR (100 MHz, CDCl3) δ 201.0, 173.2, 171.7, 161.2, 158.7, 148.5, 140.8, 139.3, 130.4, 127.9, 127.4 (d,J= 7.7 Hz), 125.4, 124.6, 123.1 (q,J= 279.7 Hz), 118.4 (d,J= 23.5 Hz), 112.7 (d,J= 25.5 Hz), 110.2 (d,J= 7.9 Hz), 85.5, 69.1, 67.9, 58.5 (q,J= 28.9 Hz), 28.2, 27.4;19F NMR (376 MHz, CDCl3) δ -62.76, -116.83.HRMS (ESI):[M+Na]+calcd. for [C25H21F4N3NaO4S]+: 558.1081, found: 558.1074.

3d：產(chǎn)率90%，白色固體，Mp.176.2~178.1℃。1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.17 (s, 1H), 7.79 (d,= 8.3 Hz, 1H), 7.64 (d,= 7.4 Hz, 1H), 7.42 (t,= 7.5 Hz, 1H), 7.23-7.15 (m, 2H), 6.88 (d,= 7.8 Hz, 1H), 4.47 (q,= 9.2 Hz, 1H), 3.26 (s, 3H), 2.41 (s, 3H), 1.64 (s, 9H);13C NMR (100 MHz, CDCl3) δ 201.0, 173.5, 171.7, 148.6, 143.3, 138.3, 135.0, 131.8, 130.8, 128.4, 126.0, 124.6, 124.4, 124.4, 123.2 (q,J= 279.3 Hz), 114.9, 109.3, 85.2, 69.1, 68.1, 58.5 (q,J= 28.8 Hz), 28.2, 27.2, 21.5;19F NMR (376 MHz, CDCl3) δ -62.76.HRMS (ESI):[M+Na]+calcd. for [C26H24F3N3NaO4S]+: 554.1332, found: 554.1321.

3e：產(chǎn)率93%，白色固體，Mp.173.6~174.8℃。1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.22 (d,= 8.4 Hz, 1H), 7.92 (dd,= 9.0, 4.6 Hz, 1H), 7.62 (d,= 7.5 Hz, 1H), 7.44 (t,= 7.8 Hz, 1H), 7.19 (t,= 7.6 Hz, 1H), 7.11 (td,= 8.8, 2.6 Hz, 1H), 6.91 (d,= 7.8 Hz, 1H), 4.47 (q,= 9.1 Hz, 1H), 3.28 (s, 3H), 1.64 (s, 9H);13C NMR (100 MHz, CDCl3) δ 200.1, 172.9, 171.9, 161.4, 159.0, 148.5, 143.4, 136.9, 132.0, 126.4 (d,J= 9.7 Hz), 125.5, 124.4 (d,J= 6.3 Hz), 123.1 (q,= 276.2 Hz), 117.1 (d,J= 23.2 Hz), 116.5 (d,J= 7.9 Hz), 115.6 (d,J= 26.3 Hz), 109.4, 85.6, 69.1, 67.9, 58.2 (q,J= 29.2 Hz), 28.2, 27.3;19F NMR (376 MHz, CDCl3) δ -62.78, -115.84. HRMS (ESI):[M+Na]+calcd. for [C25H21F4N3NaO4S]+: 558.1081, found: 558.1069.

2 結(jié)果與討論

2.1 化合物3a-3e的合成

利用最近報(bào)道出的新型三氟甲基砌塊3-三氟亞乙基羥吲哚和3-異硫氰基氧化吲哚類(lèi)化合物在溫和的條件下高效、快速的合成了化合物3a-3e，并收獲了高達(dá)85%~96%的產(chǎn)率，且3-三氟亞乙基羥吲哚和3-異硫氰基氧化吲哚兩個(gè)底物芳環(huán)上5位吸電子取代基（5-F）或供電子取代基（5-Me）對(duì)反應(yīng)結(jié)果影響較小。這一反應(yīng)中催化劑三乙胺的當(dāng)量可以低至 5 mol %的當(dāng)量，反應(yīng)溶劑二氯甲烷必須進(jìn)行重蒸除水。

產(chǎn)物的后處理只需要簡(jiǎn)單的旋干即可，其反應(yīng)體系比較干凈，兩個(gè)反應(yīng)底物基本發(fā)應(yīng)完全，在UV燈下通過(guò)薄層色譜監(jiān)測(cè)反應(yīng)體系中只剩下產(chǎn)物一個(gè)顯色點(diǎn)其Rf值在0.6左右。

2.2 化合物3a-3e的表征

化合物3a-3e通過(guò)核磁共振氫譜、氟譜、碳譜以及高分辨質(zhì)譜證實(shí)了其結(jié)構(gòu)的正確性。其中核磁共振氟譜均出現(xiàn)了單峰，說(shuō)明三氟甲基基團(tuán)已經(jīng)成功引入了目標(biāo)化合物中，成功構(gòu)建了4’-三氟甲基-3,2’-吡咯烷基雙螺環(huán)氧化吲哚及其衍生物。

3 小結(jié)

(1) 提出了一種合成4’-三氟甲基-3,2’-吡咯烷基雙螺環(huán)氧化吲哚及其衍生物的新方法，即利用新報(bào)道的三氟甲基砌塊3-三氟亞乙基羥吲哚和3-異硫氰基氧化吲哚類(lèi)化合物在有機(jī)小分子堿三乙胺催化下于室溫發(fā)生3+2環(huán)合加成反應(yīng)獲得。該反應(yīng)過(guò)程操作簡(jiǎn)單安全，反應(yīng)條件溫和，反應(yīng)產(chǎn)率高，反應(yīng)時(shí)間極短，反應(yīng)的原子經(jīng)濟(jì)性高，低反應(yīng)催化劑當(dāng)量。

(2) 本研究拓展合成了五個(gè)新型的含三氟甲基雙螺環(huán)吲哚衍生物化合物，證明該反應(yīng)具有較好的底物適應(yīng)性，為4’-三氟甲基-3,2’-吡咯烷基雙螺環(huán)氧化吲哚骨架的衍生物進(jìn)一步的手性方法學(xué)研究奠定基礎(chǔ)，同時(shí)為不對(duì)稱(chēng)研究該類(lèi)骨架衍生物提供了消旋體合成的方法學(xué)基礎(chǔ)。

(3) 成功地在藥物分子中具有特殊用處的三氟甲基基團(tuán)方便、快捷、高效地引入到3,2’-吡咯烷基雙螺環(huán)氧化吲哚骨架中。為更好地發(fā)現(xiàn)新藥提供更多的先導(dǎo)化合物，同時(shí)為醫(yī)藥、農(nóng)藥領(lǐng)域增添新的元素。

然而，盡管收獲了預(yù)期目標(biāo)產(chǎn)物，但依然有許多值得進(jìn)一步研究的方面。例如對(duì)于3,2’-吡咯烷基雙螺環(huán)氧化吲哚的方法學(xué)研究以及不對(duì)稱(chēng)方法學(xué)研究，進(jìn)一步拓展該類(lèi)骨架衍生物的合成以及不對(duì)稱(chēng)合成。這些都將更加完善對(duì)于螺環(huán)氧化吲哚骨架衍生物的研究。

[1] Klaus M,Christoph F,Fran?ois D. Fluorine in pharmaceuticals: Looking beyond intuition[J]. Science, 2007, 317(5846): 1881-1886.

[2] Badillo J J, Hanhan N V, Franz A K. Enantioselective synthesis of substituted oxindoles and spirooxindoles with applications in drug discovery[J]. Curr. Opin. Drug. Disc., 2010, 13(21): 758-776.

[3] Yu B, Yu D Q, Liu H M. Spirooxindoles: Promising scaffolds for anticancer agents[J]. Eur. J. Med. Chem., 2015, 97(1): 673-698.

[4] Rottmann M. Spiroindolones, a potent compound class for the treatment of malaria[J]. Science., 2010, 329(5996): 1175-1180.

[5] 朱文潤(rùn),鄧曉怡,魏江存,等. 3-二氫吡咯烷基螺環(huán)氧化吲哚及其衍生物的合成與表征[J].井岡山大學(xué)學(xué)報(bào):自然科學(xué)版,2018,39(1):32-36..

[6] 李術(shù)艷,沈淑君. 2-烯-1,4-二酮及其衍物的合成及晶體結(jié)構(gòu)[J]. 井岡山大學(xué)學(xué)報(bào):自然科學(xué)版, 2017, 38(2): 35-39.

[7] Shangary S, Qin D, McEachern D, et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition[J]. Proc. Natl. Acad. Sci. USA., 2008,105 (10): 3933-3938.

[8] Zhao Y, Liu L, Sun W, et al. Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors[J]. J. Am. Chem. Soc., 2013, 135(19): 7223-7234.

[9] Sun Q T,Li X Y,Su J H,et al. The squaramide-catalyzed 1,3-Dipolar cycloaddition of nitroalkenes with N-2,2,2-Trifluoroethylisatin ketimines : An approach for the Synthesis of 5’-Trifluoromethyl-spiro[pyrrolidin-3,2’-oxindoles][J]. Advanced Synthesis & Catalysis, 2015, 357(14): 3187-3196.

[10] Ma M X, Zhu Y Y, Sun Q T, et al. The asymmetric synthesis of CF3-containing spiro[pyrrolidin-3,2’- oxindole] through the organo- catalytic 1,3-dipolar cycloaddition reaction[J]. Chem. Commun., 2015, 51(42): 8789-8792.

[11] 龍先文,黃偉杰,朱文潤(rùn),等. 有機(jī)小分子催化構(gòu)建氧化吲哚C(3)位螺環(huán)化合物的研究進(jìn)展[J]. 化學(xué)試劑, 2017, (02): 148-156+174.

[12] Huang W J, Chen C, Lin N, et al. Asymmetric synthesis of tri?uoromethyl-substituted 3,3’- pyrrolidinyl-dispirooxindoles through organocatalytic 1,3-dipolar cycloaddition reactions[J]. Org. Chem. Front., 2017, 4(3): 472-482.

[13] Zhao J Q, Wu Z J, Zhou M Q, et al. Zn-catalyzed diastereo- and enantioselective cascade reaction of 3-Isothiocyanato oxindoles and 3-Nitroindoles: stereocontrolled syntheses of polycyclic Spiroo- xindoles[J]. Org. Lett., 2015, 17(20): 5020-5023.

[14] Zhao Y L, Lou Q X, Wang L S, et al. organocatalytic friedel-crafts alkylation/ lactonization reaction of naphthols with 3-Trifluoroethylidene oxindoles: The asymmetric Synthesis of Dihydrocoumarins[J]. Angew. Chem. Int. Ed., 2017, 56(1): 338-342.

[15] Xiao M J, Xu D F, Liang W H, et al. Organocatalytic enantioselective friedel-crafts alkylation/ lactonization reaction of hydroxyindoles with methylene oxindoles[J]. Adv. Synth. Catal., 2018, 360(5), 917-924.

[16] Atsuko A,Takayoshi A. Catalytic asymmetric exo’- selective [3+2] cycloaddition for constructing stereochemically diversified spiro[pyrrolidin-3,3’- oxindole]s [J]. Chem. Eur. J. 2012, 18(27): 8278-8282.

[17] Wang L,Shi X M,Dong W P,et al. E?cient construction of highly function alized spiro [γ-butyrolactone-pyrrolidin-3,3’-oxindole] tricyclic skeletons via an organocatalytic 1,3-dipolar cycloaddition[J]. Chem. Commun., 2013, 49(33): 3458-3460.

[18] Yang W L, Liu Y Z, Luo S,et al. The copper-catalyzed asymmetric construction of a dispiropyrrolidine skeleton via 1,3-dipolar cycloaddition of azomethine ylides to a-alkylidene succinimides[J]. Chem. Commun., 2015, 51(44): 9212-9215.

[19] Wang Y M,Zhang H H,Li C,et al. Catalytic asymmetric chemoselective 1,3-dipolar cycloadditions of an azomethine ylide with isatin-derived imines: diastereo- and enantioselective construction of a spiro[imidazolidine-2,3’-oxindole] framework[J]. Chem. Commun., 2016, 52(9): 1804-1807.

[20] Takayoshi A, Hiroki O, Atsuko A, et al. Py bidine- Cu(OTf)2-Catalyzed asymmetric [3+2] cycloaddition with imino esters : Harmony of Cu–Lewis acid and imidazolidine-nh hydrogen bonding in concerto catalysis[J]. Angew. Chem. Int. Ed. 2015, 54(5): 1595 -1599.

[21] Arun Y, Bhaskar G, Balachandran C, et al. Facile one-pot synthesis of novel dispirooxindole-pyrrolidine derivatives and their antimicrobial and anticancer activity against A549 human lung adenocarcinoma cancer cell line[J]. Bioorganic & Medicinal Chemistry Letters., 2013, 23(6):1839-1845.

[22] Satavisha K, Santanu M. Catalytic enantioselective cascade Michael/cyclization reaction of 3-isothiocyanato oxindoles with exocyclic α,β-unsaturated ketones en route to 3,2′-pyrrolidinyl bispirooxindoles[J]. Org. Biomol. Chem., 2016, 14(43): 10175-10179.

[23] Wu C L,Jing L H,Qin D B,et al. Organocatalytic asymmetric synthesis of trans-configured trispirooxindoles through a cascade Michael- cyclization reaction[J]. Tetrahedron Lett., 2016, 57(26): 2857-2860.

[24] Jiang X X, Cao Y M, Wang Y Q, et al. A unique approach to the concise synthesis of highly optically active spirooxazolines and the discovery of a more potent oxindole-type phytoalexin analogue [J]. J. Am. Chem. Soc. 2010, 132(43): 15328-15333.

[25] Chen W B, Wu Z J, Hu J, et al. Organocatalytic direct asymmetric aldol reactions of 3-isothiocyanato oxindoles to ketones: stereocontrolled synthesis of spirooxindoles bearing highly congested contiguous tetrasubstituted stereocenters [J].Org.Lett.,2011,13(9): 2472-2475.

[26] Han Y Y, Chen W B, Han W Y, et al. Highly efficient and stereoselective construction of dispiro- [oxazolidine-2-thione] bisoxindoles and dispiro [imidazolidine-2-thione]bisoxindoles[J]. Org. Lett., 2012, 14(2):490-493.

[27] Satavisha K, Santanu M. Catalytic aldol-cyclization cascade of 3-isothiocyanato oxindoles with α- ketophosphonates for the enantioselective synthesis of β-Amino-α-hydroxyphosphonates [J]. Org. Lett. 2015, 17(21): 5508-5511.

[28] Chen W B, Han W Y, Han Y Y, et al. Highly ef?cient synthesis of spiro[oxazolidine-2-thione-oxindoles] with 3-isothiocyanato oxindoles and aldehydes via an organocatalytic cascade aldol-cyclization reaction [J]. Tetrahedron., 2013, 69(26):5281-5286.

[29] Shota K, Motomu K, Shigeki M. Catalytic asymmetric synthesis of spirooxindoles via addition of isothiocyanato oxindoles to aldehydes under dinuclear nickel schiff base catalysis [J]. Chem. Asian J., 2013, 8(8): 1768-1771.

[30] Shota K, Tatsuhiko Y, Masakatsu S, et al. Catalytic asymmetric synthesis of spirooxindoles by a mannich-type reaction of isothiocyanato oxindoles [J]. Angew. Chem. Int. Ed., 2012, 51(28): 7007 -7010.

[31] Yuan X,Zhag S J, Du W, et al. Asymmetric diels–alder cycloadditions of trifluoromethylated dienophiles under trienamine catalysis[J]. Chem.-Eur. J., 2016, 22(31): 11048-11052.

Synthesis and Characterization of 4'-trifluoromethyl- substituted 3,3'-pyrrolidinyl-dispirooxindoles and Its Derivatives

ZHU Wen-qi1, DENG Xiao-yi2, WEI Jiang-cun3,*ZHU Wen-run3

(1. Shenzhen Mepod Environmental Protection Equipment Co. Ltd, Shenzhen, Guangdong 518122,China; 2. College of Pharmacy, Guangdong Pharmaceutical University,Guangzhou, Guangdong 510006,China; 3. College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, Guangxi 530200,China)

The synthesis of 4'-trifluoromethyl-substituted 3,3'-pyrrolidinyl-dispirooxindoles and its derivatives with high biological activity was explored. Under the catalysis of organic triethylamine, 3-isothiocyanato oxindoles reacted with 3-trifluoroethylidene oxindoles in dichloromethane (DCM) at room temperature, A 3+2 cyclization addition reaction was carried out to obtain a high yield (85%~96%) of 4'-trifluoromethyl-substituted 3,3'-pyrrolidinyl-dispirooxindoles. The synthesized products were characterized by1H-NMR,19F-NMR,13C-NMR and high-resolution mass spectrometry. This synthetic method is simple, efficient and environmentally friendly.

3,3'-pyrrolidinyl-dispirooxindoles; 3+2 cyclization addition; biological activity; fluorochemistry

1674-8085(2018)03-0019-05

R914.4

A

10.3969/j.issn.1674-8085.2018.03.005

2018-01-09；

2018-03-07

國(guó)家自然科學(xué)基金項(xiàng)目（81260673）；廣西中醫(yī)藥大學(xué)科研創(chuàng)新項(xiàng)目（YJS201625）

朱文岐(1994-)，男，江西瑞金人，技術(shù)員，主要從事藥學(xué)信息技術(shù)研究(E-mail:1844029636@qq.com);

鄧曉怡(1995-)，女，廣東廣州人，廣東藥科大學(xué)藥劑學(xué)專(zhuān)業(yè)2014級(jí)本科生(E-mail:1500718043@qq.com);

魏江存(1989-)，男，廣西賀州人，藥師，碩士，主要從事分析化學(xué)方面研究(E-mail:960837714@qq.com);

*朱文潤(rùn)(1993-)，男，江西瑞金人，藥師，碩士，主要從事藥物分子設(shè)計(jì)與手性藥物的合成研究(E-mail:2278662336@qq.com).