張 翔,李青竹,黃晴菲,何鑫磊,馬恩典,王政博,馮 鑫,李俊龍1,*,王啟衛(wèi)

(1.中國科學(xué)院 成都有機(jī)化學(xué)研究所，四川 成都 610041；2.成都大學(xué) 四川抗菌素工業(yè)研究所 抗生素研究與再評價(jià)四川省重點(diǎn)實(shí)驗(yàn)室，四川 成都 610041；3.中國科學(xué)院大學(xué)，北京 100491)

吲哚骨架廣泛存在于天然產(chǎn)物和具有生物活性和藥用價(jià)值的分子結(jié)構(gòu)中，其在農(nóng)藥、生物醫(yī)藥等領(lǐng)域中均扮演了非常重要的角色[1]。其中，吲哚并喹唑啉酮作為一類具有特殊并環(huán)骨架的喹唑啉類生物堿，具有良好的藥理活性，如抗菌[2-3]、抗真菌[4]、抗癌[5-7]以及抗利什曼原蟲[8]等。但對于此類骨架的官能團(tuán)修飾和結(jié)構(gòu)多樣性拓展尚未有較為高效的合成策略，限制了其更為深入的構(gòu)效評價(jià)及藥學(xué)相關(guān)研究的開展?；诖耍菊n題組設(shè)想在吲哚并喹唑啉骨架上引入一個(gè)易于修飾的高活性基團(tuán)，這對于豐富骨架的結(jié)構(gòu)拓展性、構(gòu)建具有多重活性的分子有重要意義。

自Wittig反應(yīng)發(fā)現(xiàn)以來[9]，磷葉立德被廣泛的應(yīng)用于碳碳鍵的構(gòu)建。除了傳統(tǒng)的與羰基化合物進(jìn)行烯基化反應(yīng)外，磷葉立德也可以作為一種富電子的親核試劑進(jìn)攻各種類型的缺電子物種[10]。此類反應(yīng)途徑不僅能夠有效提高Wittig試劑的結(jié)構(gòu)復(fù)雜性，還可以作為新型的磷葉立德進(jìn)一步通過串聯(lián)反應(yīng)構(gòu)建多官能團(tuán)化合物[11-17]。鑒于磷葉立德良好的化學(xué)轉(zhuǎn)化潛力，本課題組將磷葉立德作為修飾起點(diǎn)基團(tuán)引入吲哚并喹唑啉酮骨架，為后續(xù)制備具有此類骨架的化合物提供一種潛在的合成試劑。

本文以色胺酮(1a～1o)及酯基磷葉立德(2)為原料，經(jīng)Wittig/Michael串聯(lián)反應(yīng)，高效合成了15個(gè)含有吲哚并喹唑啉骨架的磷葉立德衍生物(3a～3o，Scheme 1)，分離收率86%～99%，其結(jié)構(gòu)經(jīng)1H NMR，13C NMR，31P NMR，19F NMR和HR-MS(ESI-TOF)確認(rèn)，其中代表化合物3a的結(jié)構(gòu)由X-ray單晶衍射確證。

Scheme 2

Scheme 1

1 實(shí)驗(yàn)部分

1.1 儀器與試劑

WRX-X-4A型熔點(diǎn)儀；JEOL-600 MHz型核磁共振儀(CDCl3為溶劑，TMS為內(nèi)標(biāo))；Waters SYNAPT G2 型高分辨質(zhì)譜儀。

化合物1a～1o和2按文獻(xiàn)[18-19]方法合成，其余所用試劑均為分析純。

1.2 合成

(1)1a～1o的合成(以1a為例)[18]

在50 mL圓底燒瓶中依次加入靛紅735.5 mg(5.0 mmol)，靛紅酸酐815.5 mg(5.0 mmol)，DABCO 448.8 mg(4.0 mmol)和乙腈20.0 mL，回流反應(yīng)12 h(TLC監(jiān)測靛紅消耗完畢)。蒸除溶劑，殘余物經(jīng)硅膠柱層析[洗脫劑：A=V(石油醚)/V(乙酸乙酯)=3/1]純化得1a。用類似的方法合成1b～1o。

(2)3a～3o的合成(以3a為例)

在10 mL反應(yīng)管中依次加入色胺酮1a24.8 mg(0.1 mmol)，三苯基膦乙酸乙酯283.6 mg(0.24 mmol)和二氯甲烷1.0 mL，于室溫下反應(yīng)2 h(TLC監(jiān)測1a消耗完畢)。反應(yīng)液經(jīng)硅膠柱層析(洗脫劑：A=2/1)純化得3a。

2-(12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3a)：黃色固體64.0 mg，收率96%，m.p.160～164 ℃；1H NMR(CDCl3,600 MHz)δ:12.05(s,1H),8.71(d,J=8.4 Hz,1H),8.35(d,J=7.8 Hz,1H),7.64～7.52(m,10H),7.44～7.37(m,6H),7.23(d,J=8.4 Hz,1H),7.09(t,J=8.4 Hz,1H),7.06(t,J=7.2 Hz,1H),6.93(t,J=6.6 Hz,1H),5.91(d,J=7.8 Hz,1H),4.28～4.18(m,3H),3.88～3.73(m,2H),1.28(t,J=7.2 Hz,3H),0.48(t,J=7.2 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.7(d,J=10.1 Hz,C=O),171.7(d,J=11.4 Hz,C=O),160.2(C=O),140.9(Ar),135.1(Ar),134.0(Ar),133.7(d,J=8.6 Hz,Ar),132.0(d,J=2.9 Hz,Ar),130.0(Ar),128.8(d,J=11.4 Hz,Ar),128.5(Ar),128.1(Ar),126.6(d,J=92.0 Hz,Ar),123.1(Ar),119.4(Ar),119.1(Ar),115.6(Ar),115.2(Ar),114.6(Ar),111.9(Ar),94.8(Ar),60.9(CH2),58.5(CH2),46.1(d,J=119.3 Hz,C=P),39.1(d,J=13.1 Hz,CH),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:25.00;HR-MS(ESI-TOF)m/z:Calcd for C41H35N2O5P{[M+Na]+}689.2176,found 689.2175。

用類似的方法合成3b～3o。

2-(8-氟-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3b)：黃色固體61.7 mg，收率90%，m.p.174～177 ℃；1H NMR(CDCl3,600 MHz)δ:12.20(s,1H),8.62(dd,J=9.0 Hz,4.8 Hz,1H),8.34(d,J=7.2 Hz,1H),7.63～7.53(m,10H),7.45～7.38(m,6H),7.24(d,J=7.8 Hz,1H),7.11(t,J=7.8 Hz,1H),6.73(td,J=9.0 Hz,2.4 Hz,1H),5.45(dd,J=9.6 Hz,1.8 Hz,1H),4.30～4.18(m,2H),4.11(d,J=18.6 Hz,1H),3.85～3.75(m,2H),1.30(t,J=6.6 Hz,3H),0.47(t,J=6.6 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.4(d,J=11.4 Hz,C=O),171.7(d,J=11.6 Hz,C=O),159.9(C=O),159.8(d,J=237.0 Hz,Ar),140.7(Ar),136.5(Ar),134.1(Ar),133.7(d,J=8.6 Hz,Ar),132.2(Ar),131.3(d,J=10.1 Hz,Ar),128.8(d,J=13.1 Hz,Ar),128.0(Ar),126.4(d,J=92.0 Hz,Ar),125.1(Ar),119.8(Ar),116.5(d,J=8.6 Hz,Ar),115.3(Ar),111.9(Ar),106.1(d,J=24.5 Hz,Ar),100.4(d,J=25.8 Hz,Ar),95.0(Ar),61.0(CH2),58.5(CH2),46.2(d,J=120.6 Hz,C=P),39.3(d,J=13.1 Hz,CH),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:24.92;19F NMR(CDCl3,564 MHz)δ:-119.61～-119.72(m,1F);HR-MS(ESI-TOF)m/z:Calcd for C41H34N2O5FP{[M+Na]+}707.2082,found 707.2074。

2-(8-氯-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3c)：黃色固體66.6 mg，收率95%，m.p.185～188 ℃；1H NMR(CDCl3,600 MHz)δ:12.25(s,1H),8.60(d,J=8.4 Hz,1H),8.33(d,J=8.4 Hz,1H),7.64～7.55(m,10H),7.46～7.39(m,6H),7.24(d,J=8.4 Hz,1H),7.11(t,J=6.6 Hz,1H),6.98(dd,J=9.0 Hz,2.4 Hz,1H),5.76(d,J=1.8 Hz,1H),4.30～4.18(m,2H),4.11(d,J=18.6 Hz,1H),3.85～3.75(m,2H),1.31(t,J=6.6 Hz,3H),0.48(t,J=7.2 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.4(d,J=10.1 Hz,C=O),171.7(d,J=12.9 Hz,C=O),160.0(C=O),140.8(Ar),136.3(Ar),134.2(Ar),133.7(d,J=8.7 Hz,Ar),132.3(d,J=2.9 Hz,Ar),131.3(Ar),129.0(Ar),128.9(d,J=13.1 Hz,Ar),128.0(Ar),127.0(Ar),126.3(d,J=92.0 Hz,Ar),119.8(Ar),118.9(Ar),116.6(Ar),115.4(Ar),114.1(Ar),111.9(Ar),94.5(Ar),61.1(CH2),58.6(CH2),46.3(d,J=120.6 Hz,C=P),39.1(d,J=12.9 Hz,CH),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:24.92;HR-MS(ESI-TOF)m/z:Calcd for C41H34N2O535ClP{[M+H]+}701.1967,found 701.1977;C41H3437ClN2O5P{[M+H]+}703.1937,found 703.1940。

2-(8-溴-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3d)：黃色固體73.9 mg，收率99%，m.p.185～187 ℃；1H NMR(CDCl3,600 MHz)δ:12.26(s,1H),8.56(d,J=7.8 Hz,1H),8.33(d,J=8.4 Hz,1H),7.63～7.56(m,10H),7.46～7.40(m,6H),7.25(d,J=8.4 Hz,1H),7.15～7.07(m,2H),5.94(d,J=1.8 Hz,1H),4.30～4.18(m,2H),4.10(d,J=18.0 Hz,1H),3.85～3.75(m,2H),1.31(t,J=6.6 Hz,3H),0.48(t,J=7.8 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.3(d,J=10.1 Hz,C=O),171.7(d,J=12.9 Hz,C=O),160.0(C=O),140.8(Ar),136.1(Ar),134.2(Ar),133.6(d,J=10.1 Hz,Ar),133.5(Ar),132.3(d,J=1.8 Hz,Ar),131.7(Ar),128.8(d,J=11.6 Hz,Ar),128.0(Ar),127.4(Ar),126.3(d,J=90.5 Hz,Ar),121.6(Ar),119.8(Ar),116.99(Ar),116.96(Ar),115.4(Ar),111.9(Ar),94.3(Ar),61.1(CH2),58.6(CH2),46.3(d,J=120.8 Hz,C=P),39.1(d,J=12.9 Hz,CH),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:24.86;HR-MS(ESI-TOF)m/z:Calcd for C41H3479N2O5BrP{[M+H]+}745.1461,found 745.1470;Calcd for C41H3481N2O5BrP{[M+H]+}747.1441,found 747.1449。

2-(8-甲基-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3e)：黃色固體62.7 mg，收率92%，m.p.179～182 ℃；1H NMR(CDCl3,600 MHz)δ:12.04(s,1H),8.56(d,J=7.8 Hz,1H),8.33(d,J=8.4 Hz,1H),7.65～7.58(m,6H),7.58～7.53(m,4H),7.45～7.38(m,6H),7.21(d,J=8.4 Hz,1H),7.08(t,J=7.8 Hz,1H),6.87(dd,J=8.4,1.2 Hz,1H),5.68(s,1H),4.23(t,J=7.2 Hz,2H),4.19(d,J=18.6 Hz,1H),3.86～3.74(m,2H),2.23(s,3H),1.29(t,J=7.8 Hz,3H),0.47(t,J=7.2 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.8(d,J=10.1 Hz,C=O),171.7(d,J=12.9 Hz,C=O),160.1(C=O),140.8(Ar),135.2(Ar),133.9(Ar),133.7(d,J=8.7 Hz,Ar),133.5(Ar),131.9(d,J=2.7 Hz,Ar),130.2(Ar),128.7(d,J=11.6 Hz,Ar),128.5(Ar),128.0(Ar),126.7(d,J=93.3 Hz,Ar),120.3(Ar),119.3(Ar),115.3(Ar),115.1(Ar),114.6(Ar),111.9(Ar),94.5(Ar),61.0(CH2),58.5(CH2),46.2(d,J=120.8 Hz,C=P),39.0(d,J=12.9 Hz,CH),21.6(CH3),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:24.92;HR-MS(ESI-TOF)m/z:Calcd for C42H37N2O5P{[M+H]+}681.2513,found 681.2524。

2-(9-氯-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3f)：黃色固體61.7 mg，收率88%，m.p.173～178 ℃；1H NMR(CDCl3,600 MHz)δ:12.12(s,1H),8.73(d,J=1.8 Hz,1H),8.32(dd,J=8.4 Hz,1.2 Hz,1H),7.61～7.53(m,10H),7.44～7.38(m,6H),7.22(d,J=7.8 Hz,1H),7.10(t,J=7.8 Hz,1H),6.88(dd,J=8.4 Hz,1.8 Hz,1H),5.75(d,J=7.8 Hz,1H),4.28～4.18(m,2H),4.16(d,J=18.0 Hz,1H),3.85～3.75(m,2H),1.29(t,J=6.6 Hz,3H),0.48(t,J=7.8 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.5(d,J=11.4 Hz,C=O),171.7(d,J=13.1 Hz,C=O),160.1(C=O),140.9(Ar),135.5(Ar),134.3(Ar),133.6(d,J=10.1 Hz,Ar),132.1(d,J=2.9 Hz,Ar),128.8(d,J=11.6 Hz,Ar),128.44(Ar),128.40(Ar),128.1(Ar),126.5(d,J=90.5 Hz,Ar),124.3(Ar),123.3(Ar),119.7(Ar),115.7(Ar),115.3(Ar),115.2(Ar),111.7(Ar),94.7(Ar),61.0(CH2),58.5(CH2),46.0(d,J=120.6 Hz,C=P),39.2(d,J=12.9 Hz,CH),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:24.92;HR-MS(ESI-TOF)m/z:Calcd for C41H3435ClN2O5P{[M+H]+}701.1967,found 701.1974;C41H3437ClN2O5P{[M+H]+}703.1937,found 703.1944。

2-(9-溴-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3g)：黃色固體64.2 mg，收率86%，m.p.181～184 ℃；1H NMR(CDCl3,600 MHz)δ:12.13(s,1H),8.88(d,J=1.2 Hz,1H),8.32(dd,J=8.4 Hz,1.8 Hz,1H),7.62～7.53(m,10H),7.44～7.38(m,6H),7.22(d,J=8.4 Hz,1H),7.11(t,J=8.4 Hz,1H),7.01(dd,J=9.0 Hz,2.4 Hz,1H),5.70(d,J=7.8 Hz,1H),4.29～4.17(m,2H),4.15(d,J=18.6 Hz,1H),3.86～3.73(m,2H),1.28(t,J=7.2 Hz,3H),0.47(t,J=7.2 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.5(d,J=11.4 Hz,C=O),171.8(d,J=11.6 Hz,C=O),160.1(C=O),140.9(Ar),135.5(Ar),134.3(Ar),133.7(d,J=10.1 Hz,Ar),132.1(d,J=2.6 Hz,Ar),129.3(Ar),128.9(d,J=12.9 Hz,Ar),128.4(Ar),128.1(Ar),126.5(d,J=92.0 Hz,Ar),126.0(Ar),119.8(Ar),118.5(Ar),115.6(Ar),115.3(Ar),111.7(Ar),111.7(Ar),94.7(Ar),61.1(CH2),58.6(CH2),46.0(d,J=120.8 Hz,C=P),39.2(d,J=12.9 Hz,CH),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:24.89;HR-MS(ESI-TOF)m/z:Calcd for C41H3479N2O5BrP{[M+H]+}745.1461,found 745.1466;Calcd for C41H3481N2O5BrP{[M+H]+}747.1441,found 747.1447。

2-(3-氟-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3h)：黃色固體60.3 mg，收率88%，m.p.167～169 ℃；1H NMR(CDCl3,600 MHz)δ:12.28(s,1H),8.66(d,J=8.4 Hz,1H),8.33(dd,J=9.0,6.6 Hz,1H),7.64～7.53(m,9H),7.45～7.38(m,6H),7.06(t,J=6.6 Hz,1H),6.92(t,J=6.6 Hz,1H),6.86(dd,J=10.2 Hz,2.4 Hz,1H),6.78(td,J=9.0 Hz,3.0 Hz,1H),5.88(d,J=7.2 Hz,1H),4.28～4.17(m,3H),3.85～3.75(m,2H),1.29(t,J=7.2 Hz,3H),0.48(t,J=6.6 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.6(d,J=11.6 Hz,C=O),171.8(d,J=11.6 Hz,C=O),166.6(d,J=251.4 Hz,Ar),159.5(C=O),142.6(d,J=12.9 Hz,Ar),134.9(Ar),133.7(d,J=10.1 Hz,Ar),132.1(d,J=3.0 Hz,Ar),131.0(d,J=10.1 Hz,Ar),129.8(Ar),128.8(d,J=11.6 Hz,Ar),126.5(d,J=92.0 Hz,Ar),123.2(Ar),119.5(Ar),115.6(Ar),114.8(Ar),108.8(Ar),108.0(d,J=23.0 Hz,Ar),100.8(d,J=25.8 Hz,Ar),95.5(Ar),61.0(CH2),58.6(CH2),46.4(d,J=120.6 Hz,C=P),39.0(d,J=12.9 Hz,CH),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:24.97;19F NMR(CDCl3,564 MHz)δ:-104.05(dd,J=17.5 Hz,8.5 Hz,1F);HR-MS(ESI-TOF)m/z:Calcd for C41H34N2O5FP{[M+Na]+}707.2082,found 707.2087。

2-(3-氯-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3i)：黃色固體65.9 mg，收率94%，m.p.173～175 ℃；1H NMR(CDCl3,600 MHz)δ:12.30(s,1H),8.67(d,J=8.4 Hz,1H),8.25(d,J=7.8 Hz,1H),7.65～7.53(m,9H),7.47～7.38(m,6H),7.23(d,J=1.8 Hz,1H),7.07(t,J=6.6 Hz,1H),7.01(dd,J=8.4 Hz,1.8 Hz,1H),6.92(t,J=6.6 Hz,1H),5.87(d,J=7.8 Hz,1H),4.31～4.17(m,3H),3.82(q,J=7.8 Hz,2H),1.30(t,J=6.6 Hz,3H),0.49(t,J=7.2 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.5(d,J=11.6 Hz,C=O),171.8(d,J=11.4 Hz,C=O),159.5(C=O),141.5(Ar),140.2(Ar),134.7(Ar),133.7(d,J=10.1 Hz,Ar),133.0(Ar),132.1(d,J=2.9 Hz,Ar),129.8(Ar),129.6(Ar),128.8(d,J=13.1 Hz,Ar),126.5(d,J=92.0 Hz,Ar),123.2(Ar),119.9(Ar),119.5(Ar),115.6(Ar),114.8(Ar),114.6(Ar),110.5(Ar),95.7(Ar),61.0(CH2),58.6(CH2),46.4(d,J=120.6 Hz,C=P),39.0(d,J=12.9 Hz,CH),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:25.09;HR-MS(ESI-TOF)m/z:Calcd for C41H3435N2O5ClP{[M+Na]+}723.1786,found 723.1783;C41H3437N2O5ClP{[M+Na]+}725.1757,found 725.1752。

2-(2-氟-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3j)：黃色固體61.0 mg，收率89%，m.p.143～147 ℃；1H NMR(CDCl3,600 MHz)δ:12.13(s,1H),8.68(d,J=8.4 Hz,1H),7.99(dd,J=9.0 Hz,3.6 Hz,1H),7.62～7.53(m,9H),7.44～7.37(m,6H),7.35～7.29(m,1H),7.19(dd,J=9.0,4.2 Hz,1H),7.06(t,J=6.6 Hz,1H),6.93(t,J=8.4 Hz,1H),5.88(d,J=8.4 Hz,1H),4.27～4.16(m,3H),3.84～3.74(m,2H),1.28(t,J=7.2 Hz,3H),0.47(t,J=7.2 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.7(d,J=10.1 Hz,C=O),171.8(d,J=11.6 Hz,C=O),159.4(C=O),156.3(d,J=237.0 Hz,Ar),137.6(Ar),135.0(Ar),133.7(d,J=10.1 Hz,Ar),132.1(d,J=2.7 Hz,Ar),130.0(Ar),128.8(d,J=12.9 Hz,Ar),128.5(Ar),126.6(d,J=90.5 Hz,Ar),123.3(Ar),122.6(d,J=25.8 Hz,Ar),119.2(Ar),116.8(d,J=7.2 Hz,Ar),115.7(Ar),114.6(Ar),112.7(d,J=24.5 Hz,Ar),112.2(d,J=7.2 Hz,Ar),94.6(Ar),61.0(CH2),58.5(CH2),46.2(d,J=120.6 Hz,C=P),39.1(d,J=12.9 Hz,CH),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:24.95;19F NMR(CDCl3,564 MHz)δ:-123.24(dd,J=10.7,6.2 Hz,1F);HR-MS(ESI-TOF)m/z:Calcd for C41H34N2O5FP{[M+Na]+}707.2082,found 707.2082。

2-(2-氯-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3k)：黃色固體66.6 mg，收率95%，m.p.171～173 ℃；1H NMR(CDCl3,600 MHz)δ:12.24(s,1H),8.67(d,J=8.4 Hz,1H),8.29(d,J=3.0 Hz,1H),7.63～7.53(m,9H),7.48(dd,J=8.4 Hz,1.8 Hz,1H),7.44～7.38(m,6H),7.17(d,J=8.4 Hz,1H),7.06(t,J=6.6 Hz,1H),6.93(t,J=8.4 Hz,1H),5.89(d,J=7.8 Hz,1H),4.28～4.17(m,3H),3.84～3.74(m,2H),1.29(t,J=6.6 Hz,3H),0.47(t,J=7.8 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.6(d,J=10.1 Hz,C=O),171.8(d,J=12.9 Hz,C=O),159.1(C=O),139.4(Ar),134.7(Ar),134.2(Ar),133.7(d,J=8.7 Hz,Ar),132.1(d,J=2.7 Hz,Ar),131.9(Ar),129.9(Ar),128.8(d,J=11.6 Hz,Ar),127.3(Ar),126.5(d,J=91.8 Hz,Ar),124.3(Ar),123.3(Ar),119.4(Ar),116.8(Ar),115.7(Ar),114.7(Ar),112.7(Ar),95.3(Ar),61.0(CH2),58.6(CH2),46.3(d,J=120.8 Hz,C=P),39.1(d,J=13.1 Hz,CH),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:24.97;HR-MS(ESI-TOF)m/z:Calcd for C41H3435ClN2O5P{[M+Na]+}723.1786,found 723.1793;C41H3437N2O5ClP{[M+Na]+}725.1757,found 725.1748。

2-(2-溴-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3l)：黃色固體67.9 mg，收率91%，m.p.174～178 ℃；1H NMR(CDCl3,600 MHz)δ:12.26(s,1H),8.67(d,J=7.8 Hz,1H),8.44(d,J=3.0 Hz,1H),7.63～7.53(m,10H),7.44～7.38(m,6H),7.11(d,J=9.0 Hz,1H),7.06(t,J=6.6 Hz,1H),6.93(t,J=8.4 Hz,1H),5.89(d,J=7.8 Hz,1H),4.27～4.16(m,3H),3.85～3.73(m,2H),1.29(t,J=6.6 Hz,3H),0.47(t,J=6.6 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.5(d,J=10.1 Hz,C=O),171.8(d,J=12.9 Hz,C=O),159.0(C=O),139.7(Ar),136.8(Ar),134.6(Ar),133.7(d,J=8.6 Hz,Ar),132.1(d,J=1.5 Hz,Ar),130.4(Ar),129.9(Ar),128.8(d,J=12.9 Hz,Ar),128.4(Ar),126.4(d,J=92.0 Hz,Ar),123.3(Ar),119.4(Ar),117.0(Ar),115.7(Ar),114.8(Ar),113.2(Ar),111.2(Ar),95.5(Ar),61.0(CH2),58.6(CH2),46.3(d,J=119.3 Hz,C=P),39.1(d,J=14.4 Hz,CH),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:24.97;HR-MS(ESI-TOF)m/z:Calcd for C41H3479N2O5BrP{[M+Na]+}767.1281,found 767.1277;Calcd for C41H3481N2O5BrP{[M+Na]+}769.1260,found 769.1255。

2-(2-甲基-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3m)：黃色固體64.0 mg，收率94%，m.p.149～154 ℃；1H NMR(CDCl3,600 MHz)δ:11.89(s,1H),8.70(d,J=8.4 Hz,1H),8.14(s,1H),7.62～7.52(m,9H),7.42～7.36(m,7H),7.14(d,J=9.0 Hz,1H),7.04(t,J=7.2 Hz,1H),6.91(t,J=8.4 Hz,1H),5.89(d,J=7.8 Hz,1H),4.25～4.16(m,3H),3.85～3.73(m,2H),2.43(s,3H),1.27(t,J=7.2 Hz,3H),0.46(t,J=7.8 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.9(d,J=11.6 Hz,C=O),171.7(d,J=13.1 Hz,C=O),160.4(C=O),138.9(Ar),135.5(Ar),135.3(Ar),133.7(d,J=8.6 Hz,Ar),132.0(d,J=2.6 Hz,Ar),130.1(Ar),128.8(d,J=12.9 Hz,Ar),128.5(Ar),128.4(Ar),127.4(Ar),126.7(d,J=90.5 Hz,Ar),123.1(Ar),118.8(Ar),115.6(Ar),115.1(Ar),114.5(Ar),111.7(Ar),94.2(Ar),61.0(CH2),58.5(CH2),46.1(d,J=119.3 Hz,C=P),39.2(d,J=14.3 Hz,CH),20.8(CH3),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:24.83;HR-MS(ESI-TOF)m/z:Calcd for C42H37N2O5P{[M+H]+}681.2513,found 681.2516。

2-(1-氯-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3n)：黃色固體65.2 mg，收率93%，m.p.179～181 ℃；1H NMR(CDCl3,600 MHz)δ:12.29(s,1H),8.73(d,J=8.4 Hz,1H),7.62～7.53(m,9H),7.44～7.35(m,7H),7.12(d,J=7.8 Hz,1H),7.09～7.02(m,2H),6.92(t,J=6.6 Hz,1H),5.87(d,J=7.8 Hz,1H),4.26～4.15(m,3H),3.83～3.73(m,2H),1.27(t,J=7.8 Hz,3H),0.46(t,J=6.6 Hz,3H);13C NMR(CDCl3,150 MHz)δ:173.6(d,J=11.6 Hz,C=O),171.8(d,J=12.9 Hz,C=O),158.3(C=O),143.2(Ar),135.8(Ar),133.9(Ar),133.7(d,J=10.1 Hz,Ar),133.3(Ar),132.1(d,J=1.8 Hz,Ar),129.9(Ar),129.1(Ar),128.8(d,J=12.9 Hz,Ar),126.5(d,J=92.0 Hz,Ar),123.2(Ar),122.5(Ar),119.4(Ar),116.0(Ar),114.6(Ar),114.5(Ar),108.4(Ar),95.0(Ar),61.0(CH2),58.5(CH2),46.5(d,J=120.6 Hz,C=P),39.0(d,J=13.1 Hz,CH),14.4(CH3),14.0(CH3);31P NMR(CDCl3,243 MHz)δ:24.97;HR-MS(ESI-TOF)m/z:Calcd for C41H3435N2O5ClP{[M+Na]+}723.1786,found 723.1777;C41H3437N2O5ClP{[M+Na]+}725.1757,found 725.1749。

2-(3,4-二甲基-12-氧代-5,12-二氫吲哚并[2,1-b]喹唑啉-6-基)-3-(三苯基-λ5-膦叉)琥珀酸二乙酯(3o)：黃色固體60.5 mg，收率87%，m.p.168～170 ℃；1H NMR(CDCl3,600 MHz)δ:11.37(s,1H),8.73(d,J=7.8 Hz,1H),8.15(d,J=7.8 Hz,1H),7.68～7.61(m,6H),7.59～7.53(m,3H),7.46～7.39(m,6H),7.06(t,J=7.8 Hz,1H),6.96(d,J=7.8 Hz,1H),6.90(t,J=8.4 Hz,1H),5.82(d,J=7.2 Hz,1H),4.33～4.18(m,3H),3.85～3.70(m,2H),2.51(s,3H),2.43(s,3H),1.27(t,J=7.8 Hz,3H),0.43(t,J=7.8 Hz,3H);13C NMR(CDCl3,150 MHz)δ:174.0(d,J=10.1 Hz,C=O),171.3(d,J=12.9 Hz,C=O),160.5(C=O),142.7(Ar),139.8(Ar),134.9(Ar),133.7(d,J=8.7 Hz,Ar),131.9(d,J=1.5 Hz,Ar),130.2(Ar),128.7(d,J=11.6 Hz,Ar),128.6(Ar),126.9(d,J=90.5 Hz,Ar),124.9(Ar),122.9(Ar),122.0(Ar),121.5(Ar),119.1(Ar),115.6(Ar),114.5(Ar),110.3(Ar),95.0(Ar),60.8(CH2),58.3(CH2),45.4(d,J=122.0 Hz,C=P),39.4(d,J=12.9 Hz,CH),21.2(CH3),14.4(CH3),13.9(CH3),13.3(CH3);31P NMR(CDCl3,243 MHz)δ:24.52;HR-MS(ESI-TOF)m/z:Calcd for C43H39N2O5P{[M+Na]+}717.2489,found 717.2482。

2 結(jié)果與討論

2.1 反應(yīng)條件優(yōu)化

以3a的合成反應(yīng)為模板反應(yīng)，對反應(yīng)進(jìn)行了考察。從表1可見，無論是在非極性溶劑，中等極性溶劑，還是極性溶劑中，色胺酮均能夠在相應(yīng)的時(shí)間內(nèi)消耗完畢，順利轉(zhuǎn)化得到3a。在極性溶劑乙腈及二甲基亞砜中反應(yīng)時(shí)，能以78%～87%的收率得到目標(biāo)產(chǎn)物(Entry 6～7)。在醚類溶劑四氫呋喃和1,4-二氧六環(huán)中反應(yīng)時(shí)，不僅反應(yīng)時(shí)間大幅延長，且收率嚴(yán)重下降(Entry 4～5)。當(dāng)以甲苯作為為溶劑時(shí)，底物的溶解性不佳，導(dǎo)致反應(yīng)時(shí)間較長(Entry 1)。在溶解性較好的二氯甲烷和氯仿中反應(yīng)時(shí)(Entry 2～3)，反應(yīng)能夠高效的進(jìn)行，收率優(yōu)異(82%～96%)。因此，將二氯甲烷作為最優(yōu)溶劑，于室溫下進(jìn)行反應(yīng)。

表1 3a合成反應(yīng)條件的優(yōu)化Table 1 Optimization of the synthesis condition of 3a

2.2 底物擴(kuò)展

在優(yōu)化的條件下，對反應(yīng)的底物普適性進(jìn)行了研究,結(jié)果見Scheme 1。首先以吲哚環(huán)上不同取代位點(diǎn)及不同電子效應(yīng)基團(tuán)為底物進(jìn)行反應(yīng)，均能以良好到優(yōu)秀的收率分離得到目標(biāo)化合物3b～3g，最高可達(dá)99%(3d)。隨后，進(jìn)一步對喹唑啉環(huán)不同取代位點(diǎn)及不同電子效應(yīng)基團(tuán)的底物兼容性進(jìn)行了考查(3i～3o)，結(jié)果表明反應(yīng)對喹唑啉環(huán)上的取代基同樣表現(xiàn)出較好的普適性(87%～95%)，對于雙取代的色胺酮3o，反應(yīng)收率也未收到明顯影響(87%)。

2.3 產(chǎn)物結(jié)構(gòu)

通過對產(chǎn)物3a(CCDC:1974569)進(jìn)行X射線單晶衍射實(shí)驗(yàn)，我們確證了產(chǎn)物的分子結(jié)構(gòu)(圖1)。其余化合物的分子結(jié)構(gòu)通過類推得到。

圖1 化合物3a的單晶結(jié)構(gòu)Figure 1The crystal structure of compound 3a

2.4 反應(yīng)機(jī)理

根據(jù)實(shí)驗(yàn)結(jié)果和文獻(xiàn)[20]報(bào)道，提出了該反應(yīng)可能的反應(yīng)機(jī)理(Scheme 2)。首先，色胺酮3a與三苯基膦乙酸乙酯2發(fā)生Wittig反應(yīng)，在吲哚并喹唑啉骨架上引入酯烯基，得到中間體Ⅰ；隨后，中間體Ⅰ與另一分子的三苯基膦乙酸乙酯發(fā)生Michael加成，得兩性離子中間體Ⅱ；最后，中間體Ⅱ通過分子內(nèi)質(zhì)子轉(zhuǎn)移得到目標(biāo)化合物3a。

通過色胺酮與酯基Wittig試劑的Wittig/Michael串聯(lián)反應(yīng)，高效合成了一系列吲哚并喹唑啉骨架的磷葉立德衍生物。該反應(yīng)普適性較好、操作簡單、條件溫和，為后續(xù)制備具有此類骨架的化合物提供了一種潛在的合成試劑。