夏綠露，王良能，李增增，李榮杰，盛回香，吳亞琴，李 培，李 玲，唐 石

(化學(xué)國家級(jí)實(shí)驗(yàn)教學(xué)示范中心，湖南 吉首 416000)

1 合成路線

圖1示出雙重叔烷基化異喹啉二酮的合成路線.

圖1 雙重叔烷基化異喹啉二酮的合成Fig. 1 Synthesis of Dual Tert-Alkylated Isoquinolinediones

2 實(shí)驗(yàn)部分

2.1 儀器和試劑

實(shí)驗(yàn)中所用的芳基酰氯、草酰氯、烷基胺、芳基胺和偶氮試劑購自阿拉丁試劑公司或百靈威試劑公司，其他試劑除特殊標(biāo)明外均為分析純.實(shí)驗(yàn)中所需的原料N-丙烯酰基-N-丁基苯甲酰胺(1a-1q)參照相關(guān)文獻(xiàn)報(bào)道方法[11]合成得到.主要儀器：AV ANCE 400 MHz 超導(dǎo)傅里葉數(shù)字化核磁共振儀(瑞士Bruker公司)；GC-MS-QP2010型質(zhì)譜儀(日本島津公司)；RE-52AA型旋轉(zhuǎn)蒸發(fā)儀(上海亞榮生化儀器廠)；XT5A型顯微熔點(diǎn)儀(北京市科儀電光學(xué)儀器廠).

2.2 目標(biāo)產(chǎn)物3的合成

以產(chǎn)物3a合成為例，在反應(yīng)管中依次加入CuI(摩爾分?jǐn)?shù)10%),Fe(NH4)2SO4·6H2O(摩爾分?jǐn)?shù)10%)，KF(2 equiv)，K3PO4(2 equiv)，1,1-偶氮二異丁腈(2a)(4 equiv),N-丙烯?；?N-烷基氯代苯甲酰胺(1a)(0.3 mmol)，最后加入溶劑二氧六環(huán) (2.0 mL)，于空氣環(huán)境下在90 ℃的油浴鍋中反應(yīng) (通常18～20 h)，經(jīng)TLC檢驗(yàn)反應(yīng)完全后，經(jīng)硅膠色譜柱分離，洗脫劑石油醚∶乙酸乙酯(7∶1)時(shí)，以78%產(chǎn)率得到最終目標(biāo)產(chǎn)物3a.產(chǎn)物為無色固體.

2.3 產(chǎn)物的表征數(shù)據(jù)

產(chǎn)物 (3a).無色固體;m.p.77.2～78.6 ℃.1H NMR (400 MHz,CDCl3) δ:8.35 (d,J=2.0 Hz,1H),7.86 (dd,J=8.4,2.0 Hz,1H),7.56 (d,J=8.4 Hz,1H),4.05～4.01 (m,2H),2.77 (d,J=14.8 Hz,1H),2.34 (d,J=14.8 Hz,1H),1.81 (s,3H),1.79 (s,3H),1.66～1.58 (m,5H),1.47～1.38 (m,2H),1.16 (s,6H),0.97 (t,J=7.4 Hz,3H);13C NMR (101 MHz,CDCl3) δ:175.1,163.3,142.0,140.6,131.2,127.6,125.5,125.4,123.9,123.3,49.5,45.9,40.8,37.0,33.5,30.6,29.8,29.6,29.2,28.8,27.3,20.3,13.8;HRMSm/z(ESI) calcd for C23H30N3O2[M+H]+380.233 3,found:380.232 9.

產(chǎn)物 (3b).白色固體;m.p.75.0～76.7 ℃.1H NMR (400 MHz,CDCl3) δ:8.38 (d,J=2.4 Hz,1H),7.87 (dd,J=8.4,2.4 Hz,1H),7.56 (d,J=8.4 Hz,1H),7.48 (d,J=7.2 Hz,2H),7.33～7.25 (m,3H),5.32 (d,J=13.6 Hz,1H),5.16 (d,J=13.6 Hz,1H),2.73 (d,J=14.4 Hz,1H),2.34 (d,J=14.8 Hz,1H),1.80 (d,J=7.2 Hz,6H),1.62 (s,3H),1.12 (s,3H),0.96 (s,3H);13C NMR (101 MHz,CDCl3) δ:175.0,163.3,142.1,140.5,136.5,131.4,129.2,128.4,127.7,125.7,125.2,123.8,123.3,49.8,46.0,44.0,37.0,33.3,30.5,29.7,29.2,28.8,26.9;HRMSm/z(ESI) calcd for C26H28N3O2[M+H]+414.217 7,found:414.217 9.

產(chǎn)物 (3c).無色油狀液體;1H NMR (400 MHz,CDCl3) δ:8.23 (s,1H),7.35 (s,1H),4.02～3.99 (m,2H),2.76 (s,4H),2.35 (d,J=14.8 Hz,1H),1.90 (s,3H),1.81 (s,3H),1.60～1.58 (m,5H),1.42～1.36 (m,2H),1.19 (s,3H),1.12 (s,3H),0.96 (t,J=7.3 Hz,3H);13C NMR (101 MHz,CDCl3) δ:175.3,163.4,143.3,140.2,138.8,131.0,125.8,123.9,123.5,122.9,49.0,45.7,40.7,34.6,33.4,30.6,29.9,29.6,28.2,28.1,26.8,21.6,20.3,13.8;HRMSm/z(ESI) calcd for C24H32N3O2[M+H]+394.249 0,found:394.248 8.

產(chǎn)物 (3d).無色油狀液體;1H NMR (400 MHz,CDCl3) δ:8.36 (s,1H),7.59 (s,1H),4.04～3.99 (m,2H),2.77 (d,J=14.8 Hz,1H),2.30 (d,J=14.8 Hz,1H),1.96 (s,3H),1.90 (s,3H),1.66～1.60 (m,5H),1.41 (dd,J=14.2,7.2 Hz,2H),1.21 (s,3H),1.18 (s,3H),0.97 (t,J=7.2 Hz,3H);13C NMR (101 MHz,CDCl3) δ:174.5,162.6,142.0,139.7,137.8,130.2,127.9,123.8,123.1,122.6,49.4,45.8,40.9,35.5,33.3,30.5,29.9,29.5,27.5,27.3,27.1,20.3,13.8;HRMSm/z(ESI) calcd for C23H29ClN3O2[M+H]+414.194 3,found:414.194 1.

產(chǎn)物 (3e).無色油狀液體;1H NMR (400 MHz,CDCl3) δ:8.41 (s,1H),7.38 (d,J=1.6 Hz,1H),4.05～4.01 (m,2H),2.80 (d,J=14.8 Hz,1H),2.24 (d,J=14.8 Hz,1H),1.89 (s,3H),1.84 (s,3H),1.63～1.56 (m,5H),1.46～1.39 (m,2H),1.21 (s,3H),1.18 (s,3H),0.98 (t,J=7.4 Hz,3H);13C NMR (101 MHz,CDCl3) δ:174.4,162.3,151.4,143.2,132.2,128.7,128.6,122.9,122.8,122.7,116.5,49.7,46.1,40.9,33.9,33.3,30.5,29.8,29.5,27.7,27.4,27.3,20.3,13.8;HRMSm/z(ESI) calcd for C24H29F3N3O3[M+H]+464.215 6,found:464.215 9.

產(chǎn)物 (3f).無色油狀液體;1H NMR (400 MHz,CDCl3) δ:8.39 (d,J=8.0 Hz,1H),7.28 (d,J=6.4 Hz,1H),4.03～3.99 (m,2H),2.75 (d,J=14.8 Hz,1H),2.27 (d,J=14.4 Hz,1H),1.87 (s,3H),1.83 (s,3H),1.65～1.57 (m,5H),1.40 (dd,J=14.8,7.2 Hz,2H),1.22 (s,3H),1.16 (s,3H),0.97 (t,J=7.4 Hz,3H);13C NMR (101 MHz,CDCl3) δ:174.6,165.3,162.7,162.4,143.8,129.3,128.9,123.1,121.4,115.3,49.7,45.9,40.8,33.9,33.3,30.5,30.0,29.6,27.3,27.1,26.9,20.3,13.8;HRMSm/z(ESI) calcd for C23H29FN3O2[M+H]+398.223 9,found:398.224 1.

產(chǎn)物(3g).無色油狀液體;1H NMR (400 MHz,CDCl3) δ:8.34 (d,J=2.0 Hz,1H),7.86 (dd,J=8.4,2.4 Hz,1H),7.55 (d,J=8.4 Hz,1H),4.05～4.01 (m,2H),2.74 (d,J=14.8 Hz,1H),2.33 (d,J=14.8 Hz,1H),2.21 (d,J=7.2 Hz,2H),1.89～1.85 (m,8H),1.64～1.57(m,12H),1.44～1.38 (m,5H),0.97 (t,J=7.3 Hz,3H);13C NMR (101 MHz,CDCl3) δ:175.3,163.4,141.8,140.9,131.6,127.4,125.9,125.2,122.2,121.4,49.7,45.6,44.1,40.7,38.3,37.5,36.9,36.5,35.8,33.7,29.6,24.8,24.7,23.5,23.4,22.7,22.5,20.3,13.8;HRMSm/z(ESI) calcd for C29H38N3O2[M+H]+460.295 9,found:460.295 7.

產(chǎn)物 (3h).無色油狀液體；1H NMR (400 MHz,CDCl3) δ:8.24 (d,J=2.0 Hz,1H),7.54 (dd,J=8.4,2.4 Hz,1H),7.32～7.28 (m,1H),3.99 (td,J=7.2,3.2 Hz,2H),3.67 (s,3H),3.13 (s,3H),2.64 (q,J=14.4 Hz,2H),1.65～1.57 (m,8H),1.54 (s,3H),1.43～1.36 (m,2H),1.05 (s,3H),0.97 (t,J=7.4 Hz,3H),0.89 (s,3H);13C NMR (101 MHz,CDCl3) δ:177.0,176.6,176.0,163.9,144.0,140.2,131.1,127.0,125.7,124.7,52.3,51.4,50.5,46.4,45.8,41.6,40.5,33.7,29.6,29.2,26.4,26.3,23.2,20.4,13.8;HRMSm/z(ESI) calcd for C25H36NO6[M+H]+446.253 8,found:446.254 0.

產(chǎn)物 (3i).無色油狀液體(d.r.= 1∶1)；1H NMR (400 MHz,CDCl3) δ:8.34 (d,J=2.0 Hz,0.5H),8.29 (d,J=2.0 Hz,0.5H),7.85 (dd,J=8.4,2.4 Hz,0.5H),7.80 (dd,J=8.0,2.0 Hz,0.5H),7.57 (d,J=8.0 Hz,0.5H),7.53 (d,J=8.4 Hz,0.5H),4.06～4.01 (m,2H),2.85 (d,J=14.4 Hz,0.5H),2.67 (d,J=14.8 Hz,0.5H),2.43 (d,J=14.8 Hz,0.5H),2.23 (d,J=14.4 Hz,0.5H),2.06～2.00 (m,2H),1.80 (s,1.5H),1.76 (s,1.5H),1.66～1.60 (m,6H),1.45～1.39 (m,4H),1.05 (d,J=7.2 Hz,2H),1.00～0.96 (m,9H);13C NMR (101 MHz,CDCl3) δ:175.5,175.0,163.4,140.5,131.7,127.6,125.7,125.2,122.7,122.2,48.6,47.7,45.8,43.2,40.8,35.5,33.7,29.6,26.9,26.0,23.4,20.4,13.8,9.8,9.0;HRMSm/z(ESI) calcd for C25H34N3O2[M+H]+408.264 6,found:408.264 3.

3 結(jié)果與討論

3.1 反應(yīng)條件探索

以N-丙烯?；?N-丁基-3氯代苯甲酰胺1a與偶氮二異丁腈2a的加成/環(huán)化反應(yīng)為模板反應(yīng)來探索最佳反應(yīng)條件(表1).筆者使用CuI作為催化劑，dioxane(二氧六環(huán))作為溶劑，K3PO4為堿對(duì)反應(yīng)進(jìn)行嘗試，幸運(yùn)的是，通過GC-MS檢測(cè)發(fā)現(xiàn)有少量目標(biāo)產(chǎn)物3a生成.為了進(jìn)一步提升反應(yīng)產(chǎn)率，筆者又進(jìn)行了大量的嘗試，發(fā)現(xiàn)以空氣為氧化劑，且加入KF時(shí)更有利于目標(biāo)產(chǎn)物異喹啉二酮的生成.因此，接著使用KF和空氣在接下來的反應(yīng)中來探索最佳條件.實(shí)驗(yàn)過程中嘗試添加了不同種類的助催化劑(如LiBr,MnSO4,FeS,SnCl2·2H2O,Fe(NH4)2SO4·6H2O等)，結(jié)果顯示，不同的助催化劑對(duì)反應(yīng)有不同程度的影響，尤其是在使用Fe(NH4)2SO4·6H2O作為助劑時(shí)，目標(biāo)產(chǎn)物的產(chǎn)率上升至78%(entries 1～8).此外，筆者還試圖通過使用一些含氮配體(如聯(lián)吡啶，1,10-菲羅啉，三亞乙基二胺(DABCO))來提高產(chǎn)率，但未獲得成功(entries 9～11).接下來對(duì)催化劑進(jìn)行了優(yōu)化，發(fā)現(xiàn)Cu(OAc)2，CuCl和Cu2O等催化劑的效果均不如CuI(entries 12～14).除此之外，還考查了其他無機(jī)堿(如KOAc，K2CO3，Li2CO3，Cs2CO3)等對(duì)反應(yīng)的影響，發(fā)現(xiàn)K3PO4依然是最好的選擇(entries 15～18).

綜上所述，最佳反應(yīng)條件為：N-丙烯?；?N-丁基苯甲酰胺1a (0.3 mmol),偶氮二異丁腈2a (4 equiv)，CuI(摩爾分?jǐn)?shù)10%),Fe(NH4)2SO4·6H2O (摩爾分?jǐn)?shù)10%),K3PO4(2 equiv),KF (2 equiv),dioxane (二氧六環(huán))為溶劑，反應(yīng)溫度為90 ℃，空氣環(huán)境中反應(yīng)18～20 h.

表1 優(yōu)化反應(yīng)條件摸索

entryCatalystbaseadditivesolventYield of 3a/%②1CuIK3PO4/KFLiBrdioxane562CuIK3PO4/KFMnSO4dioxane553CuIK3PO4/KFFeSdioxane374CuIK3PO4/KFFe(NH4)2SO4·6H2Odioxane785CuIK3PO4/KFSnCl2·2H2Odioxane536CuIK3PO4/KFZnBr2dioxane667CuIK3PO4/KFAgFdioxane538CuIK3PO4/KFFeBr2dioxane679CuIK3PO4/KF聯(lián)吡啶dioxane6010CuIK3PO4/KF1,10菲羅啉dioxane5311CuIK3PO4/KFDABCOdioxane1212Cu(OAc)2K3PO4/KFLiBrdioxane3713Cu2OK3PO4/KFLiBrdioxane4214CuClK3PO4/KFLiBrdioxane3415CuIKOAC/KFLiBrdioxane3216CuIK2CO3/KFLiBrdioxane4717CuILi2CO3/KFLiBrdioxane3618CuICs2CO3/KFLiBrdioxane25

注：①Reaction conditions:1a (0.3 mmol),AIBN 2a (4 equiv),CuI (10%),co-catalyst (10%),O2(1 atm),base (2 equiv),KF (2 equiv),and solvent (2 mL) at 90 ℃ under air atmosphere for 18 h.②Yield of the isolated product.

3.2 反應(yīng)底物范圍

得到最佳反應(yīng)條件后，接著考察了反應(yīng)底物的適用范圍(圖2).初步篩選表明：氮原子上帶有n-Bu，Bn取代時(shí)，均能以適中產(chǎn)率得到目標(biāo)產(chǎn)物(產(chǎn)物3a，3b).除了利用AIBN(偶氮二異丁基)為偶氮試劑之外，還嘗試?yán)闷渌嫉噭橥榛杂苫?，發(fā)現(xiàn)反應(yīng)仍然保持較高的活性，分別以中等以上的產(chǎn)率得到產(chǎn)物(產(chǎn)物3g，3h，3i).

非常值得一提的是，此偶聯(lián)反應(yīng)表現(xiàn)驚奇的區(qū)域選擇性.當(dāng)丙烯?；郊柞０返谋江h(huán)上3,4位上連有2個(gè)鹵原子或者其他鹵素時(shí)，反應(yīng)總是在3位鹵原子發(fā)生自由基偶聯(lián)反應(yīng)引入叔烷基基團(tuán).甚至當(dāng)4位連有更活潑的鹵元素(如F)，而3位連有較惰性的鹵元素(如Cl)的時(shí)候，反應(yīng)依然遵循以上所述的區(qū)域選擇性，即3位選擇性發(fā)生烷基化偶聯(lián)反應(yīng)，以適中產(chǎn)率得到了一系列異喹啉二酮化合物(產(chǎn)物3c，3d，3e，3f).

圖2 底物N-烯丙酰基苯甲酰胺及烷基偶氮試劑的適應(yīng)范圍Fig. 2 Scope of Methacryloyl Benzamides and Alkyl azo Reagents

3.3 反應(yīng)機(jī)理推測(cè)

為了探測(cè)反應(yīng)機(jī)理，進(jìn)行了如圖3所示的控制試驗(yàn).結(jié)果顯示加入過量自由基清除劑TMEPO(2,2,6,6-四甲基哌啶-氮氧化物)時(shí),此環(huán)化反應(yīng)幾乎不能發(fā)生，此現(xiàn)象表明此反應(yīng)應(yīng)該經(jīng)歷了一個(gè)自由基歷程.

圖3 有關(guān)產(chǎn)物3a形成的控制實(shí)驗(yàn)Fig. 3 Control Experiment for the Formation of 3a

圖4 叔烷基化異喹啉二酮3a形成的可能機(jī)理過程Fig. 4 Proposed Mechanism for the Formation of Tert-Alkylating Isoquinolinedione 3a

4 結(jié)論

筆者首次發(fā)展了一種高效的CuI/Fe(NH4)2SO4·6H2O/air協(xié)同催化合成官能化異喹啉-1,3(2H,4H)二酮的新途徑.此反應(yīng)以烷基偶氮試劑為α-取代叔烷基自由基源物質(zhì)，在廉價(jià)銅/鐵/空氣體系協(xié)同催化氧化下，N-丙烯?；?N-丁基-3氯代苯甲酰胺經(jīng)歷一個(gè)由自由基加成引發(fā)的、繼而去芳構(gòu)化/自由基碳-碳偶聯(lián)/重新芳構(gòu)化的串聯(lián)過程，一步成功構(gòu)筑了多重α-官能化碳(叔)—碳鍵，得到了一系列7位叔烷基化異喹啉二酮衍生物.此反應(yīng)底物適應(yīng)范圍廣，反應(yīng)操作簡單、原料易得，為發(fā)現(xiàn)功能化異喹啉二酮類先導(dǎo)化合物提供了參考.