賈義霞，李英龍，劉人榮

(浙江工業(yè)大學(xué) 化學(xué)工程學(xué)院，浙江 杭州 310014)

鈀催化吲哚的去芳香化雙芳基化

賈義霞，李英龍，劉人榮

(浙江工業(yè)大學(xué) 化學(xué)工程學(xué)院，浙江 杭州 310014)

以鈀為催化劑,三環(huán)己基膦為配體,芳基硼酸為芳基化試劑,通過吲哚的分子內(nèi)Heck/Suzuki串聯(lián)反應(yīng)實(shí)現(xiàn)了吲哚的雙官能團(tuán)化,為合成結(jié)構(gòu)多樣性的吲哚啉衍生物提供了一種高效、快捷的方法.通過簡單起始原料出發(fā)，高產(chǎn)率、高對(duì)映選擇性地合成了一系列的含有連續(xù)叔碳/季碳中心的吲哚林化合物.并系統(tǒng)地研究了反應(yīng)的溶劑、堿和配體對(duì)反應(yīng)的影響以及底物中各種給電子或吸電子基團(tuán)對(duì)產(chǎn)物收率的影響.重要的是,通過該反應(yīng)可以順利實(shí)現(xiàn)克級(jí)規(guī)模制備，體現(xiàn)了方法的優(yōu)越性及可靠性.

鈀催化;吲哚;芳基化;去芳構(gòu)化;串聯(lián)反應(yīng)

吲哚啉廣泛存在于具有生物活性天然產(chǎn)物以及藥物活性分子中,并常用作醫(yī)藥或農(nóng)藥合成的中間體,近年來一直受到化學(xué)家們的廣泛關(guān)注[1-4].大多數(shù)已報(bào)道的合成吲哚啉方法往往需要多步合成才能得以實(shí)現(xiàn),發(fā)展高效、快速構(gòu)建吲哚啉的合成方法具有重要意義[5].近年來,過渡金屬催化的吲哚去芳構(gòu)化反應(yīng)已經(jīng)成為合成具有吲哚啉骨架類化合物的一種重要方法[6].2011年,Bedford小組利用鈀催化的偶聯(lián)反應(yīng)實(shí)現(xiàn)了2-氨基-1,3-二甲基吲哚的去芳構(gòu)化[7].2012年,You小組報(bào)道了鈀催化的3-取代吲哚的去芳構(gòu)化反應(yīng),以最高93%的收率獲得去芳構(gòu)化產(chǎn)物[8].2015年,筆者課題組報(bào)道了Pd催化的N-取代吲哚的不對(duì)稱去芳構(gòu)化反應(yīng)[9],基于受阻的碳-氫活化的策略首次實(shí)現(xiàn)了吲哚的去芳構(gòu)化還原Heck反應(yīng),合成了具有季碳手性中心的吲哚啉類化合物.隨后,Lautens課題組以氰化鋅為氰基化試劑,首次實(shí)現(xiàn)了吲哚2,3-位的去芳構(gòu)化雙官能化反應(yīng)[10].梁永民小組[11]和筆者小組[12]也分別通過脫羧偶聯(lián)和sonogashira偶聯(lián)反應(yīng)對(duì)芐基鈀中間體進(jìn)行捕獲,實(shí)現(xiàn)了吲哚2,3-位的去芳構(gòu)化/炔基化反應(yīng).最近,Lautens小組又進(jìn)一步采用芳基硼酸酯為試劑對(duì)反應(yīng)中形成的芐基鈀中間體進(jìn)行捕獲,高非對(duì)映選擇性地完成了吲哚去芳基化/Suzuki偶聯(lián)串聯(lián)反應(yīng)[13].在Lautens課題組進(jìn)行研究的同時(shí),筆者也對(duì)吲哚的2，3-位去芳構(gòu)化雙官能化反應(yīng)進(jìn)行研究,與Lautens課題組不同的是筆者采用更便宜的芳基硼酸為底物,以及更簡單的醋酸鈀/三環(huán)己基膦為催化劑,通過吲哚的分子內(nèi)去Heck/Suzuki串聯(lián)反應(yīng)高非對(duì)映選擇性地實(shí)現(xiàn)了吲哚的雙官能團(tuán)化.

1 實(shí)驗(yàn)部分

1.1 實(shí)驗(yàn)試劑及儀器

儀器:Bruker Advance Ш 500 MHz型核磁共振儀(TMS作為內(nèi)標(biāo),CDCl3作為溶劑)柱色譜為柱層析硅膠(用200～300目硅膠,青島海洋化工),所有反應(yīng)均在常規(guī)玻璃儀器中進(jìn)行,采用磁力攪拌.

主要試劑：各類含不同取代基的吲哚、不同取代的鄰溴苯甲酸、苯硼酸、醋酸鈀、膦配體及各類有機(jī)溶劑等(所用試劑均為市售分析純或者化學(xué)純).

1.2 實(shí)驗(yàn)方法

鈀催化Heck/Suzuki串聯(lián)反應(yīng)對(duì)吲哚去芳香化雙官能化反應(yīng)的典型操作步驟：在安培管中依次加入0.2 mmol的取代吲哚底物Ⅰa，0.4 mmol的苯硼酸Ⅱa,0.4 mmol的K2CO3，摩爾分?jǐn)?shù)為5%的Pd(OAc)2和摩爾分?jǐn)?shù)為10%的配體PCy3·HBF4,氮?dú)獗Ｗo(hù)下,注射器加入2 mL的新蒸餾的溶劑,100 ℃下反應(yīng)12 h.反應(yīng)結(jié)束后粗產(chǎn)品用層析柱分離得到目標(biāo)產(chǎn)物，其中層析柱分離時(shí)使用的淋洗液為V(乙酸乙酯)∶V(石油醚,60～90 ℃)=1∶10.

部分產(chǎn)物表征如下:

10b-甲基-11-(苯基)-10b,11-二氫-6H-吲哚并[2,1-a]吲哚-6-酮(Ⅲaa)：白色固體,產(chǎn)率86%,Mp=176～177 ℃,1H NMR(500 MHz, CDCl3)δ7.83(d,J=8.0 Hz, 1H),7.69(d,J=7.5 Hz, 1H),7.41(t,J=7.5 Hz, 1H),7.25(dd,J=12.0,8.5 Hz,2H),7.18(d,J=7.5 Hz,1H),7.13(d,J=7.5 Hz,1H),7.06(d,J=7.5 Hz,1H),6.88～6.96(m,3H),6.55(d,J=7.0 Hz,2H),4.36(s,1H),1.76(s,3H).13C NMR(125 MHz, CDCl3)δ168.5,140.7,139.2,138.9,132.8,131.9,128.7,128.2,128.0,127.6,126.8,126.6,125.0,124.2,123.0,117.1,76.0,57.1,28.4.HRMSm/z(ESI+): Calculated for C22H17NO ([M+H]+):312.138 8, Found 312.138 3.

9-甲氧基-10b-甲基-11-(苯基)-10b,11-二氫-6H-吲哚并[2,1-a]吲哚-6-酮(Ⅲba)：白色固體,產(chǎn)率94%,Mp=135-136 ℃,94% yield;1H NMR (500 MHz, CDCl3)δ7.84 (d,J=7.9 Hz,1H),7.42(td,J=7.5,1.0 Hz,1H),7.17～7.20 (m,2H),7.14(td,J=7.0,1.0 Hz,1H),6.94～6.99(m,4H),6.85(dd,J=8.5,2.5 Hz,1H),6.55～6.58(m,2H),4.35(s,1H),3.76(s,3H),1.75(s,3H).13C NMR(125 MHz, CDCl3)δ168.4,159.8,141.1,140.8,139.2,139.0,134.2,128.6,128.2,127.6,126.8,126.6,1 250,123.8,120.4,117.0,106.7,75.6,57.0,55.5,28.5. HRMSm/z(ESI+): Calculated for C23H19NO2([M+H]+):342.149 4, Found 342.148 7.

9,10b-二甲基-11-(苯基)-10b,11-二氫-6H-吲哚并[2,1-a]吲哚-6-酮(Ⅲca)：白色固體,產(chǎn)率94%,Mp=172～173 ℃,94% yield;1H NMR(500 MHz, CDCl3)δ7.83(d,J=8.0 Hz,1H),7.58(d,J=7.5 Hz,1H),7.41(td,J=7.5,1.0 Hz,1H),7.17～7.21(m,1H),7.13(td,J=7.5,1.0 Hz,1H),7.05 (dd,J=8.0,0.5 Hz,1H),6.92～6.98 (m,3H),6.86(s,1H),6.55～6.59(m,2H),4.35(s,1H),2.26(s,3H),1.76(s,3H).13C NMR (125 MHz, CDCl3)δ168.7,149.1,142.7,140.8,139.4,138.8,130.3,129.1,128.6,128.1,127.6,126.8,126.5,124.9,124.0,123.6,117.0,75.7,57.1,28.5,21.8. HRMSm/z(ESI+): Calculated for C23H19NO([M+H]+):326.154 5, Found 326.154 2.

9-氟-10b-甲基-11-(苯基)-10b,11-二氫-6H-吲哚并[2,1-a]吲哚-6-酮(Ⅲda)：Mp=193～194 ℃,產(chǎn)率68%;1H NMR (500 MHz, CDCl3)δ7.84(d,J=8.0 Hz,1H),7.42～7.46(m,1H),7.36(dd,J=7.5,2.5 Hz,1H),7.21(dd,J=7.0,0.5 Hz,1H),7.15～7.18(m,1H),7.05(dd,J=8.0,4.5 Hz,1H),6.95～7.01(m,4H),6.56(dd,J=7.5,1.5 Hz,2H),4.37(s,1H),1.77(s,3H).13C NMR(125 MHz,CDCl3)δ167.2,167.1,162.6(d,J=246.3 Hz),144.2(d,J=2.4 Hz),140.5,138.9(d,J=19.8 Hz),135.0(d,J=8.4 Hz),128.8,128.4,127.5,127.0,126.6,125.3,124.5(d,J=8.4 Hz),119.5(d,J=24.0 Hz),117.1,110.8(d,J=25.0 Hz),75.7,57.1,28.4. HRMSm/z(ESI+): Calculated for C22H16FNO([M+H]+):330.129 4, Found 330.129 0.

10,10b-二甲基-11-(苯基)-10b,11-二氫-6H-吲哚并[2,1-a]吲哚-6-酮(Ⅲea)：Mp=180～181 ℃,產(chǎn)率49%;1H NMR(500 MHz, CDCl3)δ7.86(d,J=7.5 Hz,1H),7.66(d,J=7.5 Hz,1H),7.39(td,J=7.5,1.0 Hz,1H),7.23(t,J=7.5 Hz,1H),7.16(d,J=7.5 Hz,1H),7.08～7.11(m,2H),6.94～6.97(m,3H),6.64～6.67(m,2H),4.39(s,1H),2.27(s,3H),1.81(s,3H).13C NMR(125 MHz, CDCl3)δ167.7,146.3,140.9,140.0,138.0,134.0,133.7,132.5,128.6,128.5,128.0,127.3,126.9,126.3,124.9,122.0,117.0,76.2,56.7,26.5,19.1. HRMSm/z(ESI+): Calculated for C23H19NO([M+H]+):326.154 5, Found 326.154 0.

8,9-二甲氧基-10b-甲基-11-(苯基)-10b,11-二氫-6H-吲哚并[2,1-a]吲哚-6-酮(Ⅲfa)：Mp=180～181 ℃,產(chǎn)率96%;1H NMR(500 MHz, CDCl3)δ7.80(d,J=8.0 Hz,1H),7.40(t,J=7.5 Hz,1H),7.14～7.18(m,2H),7.12(d,J=7.5 Hz,1H),6.97(d,J=7.0 Hz,3H),6.59(d,J=6.5 Hz,2H),6.44(s,1H),4.34(s,1H),3.85(s,3H),3.77(s,3H),1.76(s,3H).13C NMR(125 MHz, CDCl3)δ169.1,152.8,149.5,143.1,141.0,139.6,138.5,128.6,128.1,127.8,126.9,126.5,124.8,124.7,116.8 105.4,105.2,75.4,57.07(s),56.1,56.0,28.7. HRMSm/z(ESI+): Calculated for C24H21NO3([M+H]+):372.160 0, Found 372.162 1.

2 結(jié)果與討論

2.1 反應(yīng)條件優(yōu)化

采用吲哚衍生物Ⅰa和苯硼酸Ⅱa作為模型底物,來研究吲哚與苯硼酸的去芳構(gòu)化串聯(lián)反應(yīng).以摩爾分?jǐn)?shù)為5%的Pd(OAc)2作為催化劑，摩爾分?jǐn)?shù)為10%的PPh3作為配體，2當(dāng)量的K2CO3作為堿,在甲苯溶劑中100 ℃下進(jìn)行12 h反應(yīng)后，能夠以66%的收率得到單一構(gòu)型的去芳構(gòu)化目標(biāo)產(chǎn)物Ⅲa(表1,序號(hào)1).受此鼓舞，首先對(duì)反應(yīng)條件中的溶劑進(jìn)行篩選，其反應(yīng)式為

表1 溶劑對(duì)產(chǎn)率的影響

序號(hào)12345溶劑TolueneDMFTHFMeOHMeCN產(chǎn)率/%664353—78

2.1.1 溶劑對(duì)產(chǎn)率的影響

當(dāng)以DMF和THF作為反應(yīng)溶劑時(shí),雖然反應(yīng)也能順利發(fā)生,但產(chǎn)率有所降低(表1,序號(hào)2,3).而以MeOH作為溶劑時(shí),反應(yīng)幾乎不能檢測(cè)到產(chǎn)物(表1,序號(hào)4).最后,當(dāng)使用MeCN作為溶劑時(shí),反應(yīng)產(chǎn)率可以得到較大提升,以78%收率得到目標(biāo)產(chǎn)物.

2.1.2 堿對(duì)產(chǎn)率的影響

接下來,以MeCN為溶劑對(duì)反應(yīng)的堿進(jìn)行考察.如表2所示，以K3PO4為堿時(shí)能夠得到與K2CO3幾乎相當(dāng)?shù)慕Y(jié)果.采用有機(jī)堿Et3N以及堿性更弱的NaHCO3為堿時(shí),反應(yīng)產(chǎn)率顯著降低.而采用更強(qiáng)堿性的Cs2CO3為堿時(shí),反應(yīng)幾乎得不到產(chǎn)物.

表2 堿對(duì)產(chǎn)率的影響

2.1.3 配體對(duì)產(chǎn)率的影響

以MeCN為溶劑，K2CO3作堿，對(duì)反應(yīng)的配體進(jìn)行考察.如表3所示，當(dāng)使用雙齒配體dppm或dppb作為配體時(shí),產(chǎn)率有所下降.而使用大位阻富電子的PCy3為配體時(shí),能以最高86%的收率得到目標(biāo)產(chǎn)物,而以PtBu3·HBF4為配體時(shí),產(chǎn)率僅有18%.

表3 配體對(duì)產(chǎn)率的影響

2.2 底物拓展

在上述最優(yōu)反應(yīng)條件下,首先對(duì)吲哚底物的普適性進(jìn)行了考察.底物Ⅰ的拓展結(jié)構(gòu)式(yield表示收率，dr表示非對(duì)映異構(gòu)體比值)為

吲哚底物含溴芳環(huán)上不論含有富電子還是吸電子取代基,均能以良好到優(yōu)異的產(chǎn)率得到去芳構(gòu)化串聯(lián)反應(yīng)產(chǎn)物.相對(duì)而言,含有給電子基團(tuán)的底物較吸電子取代基底物產(chǎn)率更高(Ⅲfa vs Ⅲda).當(dāng)芳環(huán)上含有位阻更大的鄰位取代基時(shí),反應(yīng)產(chǎn)率大幅降低(Ⅲea).除此之外,吲哚2位上的取代基為芳香取代基時(shí),同樣能以較高收率得到目標(biāo)產(chǎn)物(Ⅲga～Ⅲia),產(chǎn)率較烷基取代底物略有下降.

接下來，對(duì)芳基硼酸底物進(jìn)行考察.底物2的拓展結(jié)構(gòu)式(yield表示收率，dr表示非對(duì)映異構(gòu)體比值)為

在標(biāo)準(zhǔn)條件下，各種鄰位、對(duì)位和間位取代的芳基硼酸均能以良好到優(yōu)秀的收率得到去芳構(gòu)化目標(biāo)產(chǎn)物.含有強(qiáng)給電子(Ⅱc)或強(qiáng)吸電子基團(tuán)硼酸(Ⅱd)都使反應(yīng)產(chǎn)率有較大幅度下降.當(dāng)以對(duì)氯硼酸作為底物時(shí)，反應(yīng)的非對(duì)映選擇性較差,只能得到非對(duì)映選擇性為6∶1的去芳香化產(chǎn)物Ⅲea.總體上講，含有鄰位取代基的芳基硼酸較相應(yīng)間位或?qū)ξ划a(chǎn)率有較大幅度降低(Ⅲah vs Ⅲai)和(Ⅲaj vs Ⅲab and Ⅲag).

3 結(jié) 論

以醋酸鈀鈀為催化劑,芳基硼酸為芳基化試劑,通過吲哚的分子內(nèi)去芳構(gòu)化/芳基化串聯(lián)反應(yīng)實(shí)現(xiàn)了吲哚的雙官能團(tuán)化,高非對(duì)映選擇性地合成了一系列含有連續(xù)季碳和叔碳中心的2,3-二取代吲哚啉化合物.該反應(yīng)條件溫和、底物適用范圍較好.

[1] 沈曉燕,高建榮,韓亮,等.MCM-41的磺酸官能化及催化性能研究[J].浙江工業(yè)大學(xué)學(xué)報(bào),2011,39(6):605-608.

[2] 劉運(yùn)奎,江波,婁紹杰,等.鈀催化的喹喔啉基導(dǎo)向的鄰位碳-氫鍵乙酸化反應(yīng)[J].浙江工業(yè)大學(xué)學(xué)報(bào),2013,41(1):1-5.

[3] 高建榮,龔淵,金紅衛(wèi),等.一種合成氮丙啶衍生物的新方法[J].浙江工業(yè)大學(xué)學(xué)報(bào),2014,42(1):77-80.

[4] DALPOZZO R, BARTOLI G, BENCIVENNI G. Recent advances in organocatalytic methods for the synthesis of disubstituted 2-and 3-indolinones[J]. Chemical society reviews，2012,41,7247-7290.

[5] IYENGAR R, SCHILDKNEGT K, MORTON M, et al. Revisiting a classic approach to the aspido-sperma alkaloids: an intramolecular schmidt reaction mediated synthesis of (+)-aspi-dospermidine[J]. Journal of organic chemistry,2005,70(26):10645-10652.

[6] PAPE A R, KALIAPPAN K P, KUNDIG E P. Transition-metal-mediated dearomatization re-actions[J]. Chemical reviews,2000,100(8):2917-2940.

[7] BEDFORD R B, BUTTS C P, HADDOW M F, et al. Reactive 4a-alkyl-4aH-carbazoles by catalytic dearomatisation, and their unusual dimerisation and dealkylation reactions[J]. Chemical communications,2009,32(32)：4832-4834.

[8] WU K J, DAI L X, YOU S L. Palladium(0)-catalyzed dearomative arylation of indoles: convenient access to spiroindolenine derivatives[J]. Organic letters,2012,14(14):3772-3775.

[9] SHEN C, LIU R R, FAN R J, et al. Enantioselective arylative dearomatization of indoles via Pd-catalyzed intramolecular reductive Heck reactions[J]. Journal of the american chemical society,2015,137(15):4936-4939.

[10] PETRONE D A, YEN A, ZEIDAN N, et al. Dearomative indole bisfunctionalization via a di-astereoselective palladium-catalyzed arylcya-nation[J]. Organic letters,2015,17(19):4838-4841.

[11] CHEN S, WU X X, WANG J, et al. Palladium-catalyzed intramolecular dearomatization of indoles via decarboxylative alkynyl termi-nation[J]. Organic letters,2016,18(16):4016-4019.

[12] LIU R R, XU T F, WANG Y G, et al. Palladium-catalyzed dearomative arylalkynylation of indoles[J]. Chemical communications,2016,52(94):13664-13667.

(責(zé)任編輯：陳石平)

Palladium-catalyzed dearomative diarylation of indole

JIA Yixia, LI Yinglong, LIU Renrong

(College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China)

A novel Pd-catalyzed bisfunctionalization of indoles that proceeds via an intramolecular dearomatization/arylation cascade reaction is developed by employing Pd(OAc)2as a catalyst, PCy3as a ligand and phenylboronic acid as an arylative reagent, which provides a straightforward and efficient access to structural diversely indolines. A series of indolines bearing vicinal tertiary and quaternary stereocenters can be obtained in excellent yields and derived from easily available starting materials. A set of solvents, bases and ligands were screened to enhance the yield. The effect of substituents was also examined. Importantly, this protocol was amenable to gram-scale synthesis, showing the practicality of this reaction.

palladium-catalyzed; indole; arylation; dearomatization; cascade reaction

2016-11-01

國家自然科學(xué)基金資助項(xiàng)目(21372202)

賈義霞(1976—)，男，江蘇泰州人，教授，博士，研究方向?yàn)椴粚?duì)稱合成，E-mail:yxjia@zjut.edu.cn.

O62

A

1006-4303(2017)04-0387-04