孫宏偉, 王浩宇, 連春霞, 張曉梅, 袁偉成

(1. 中國科學(xué)院 成都有機(jī)化學(xué)研究所 不對稱合成與手性技術(shù)四川省重點(diǎn)實(shí)驗(yàn)室，四川 成都 610041;2. 中國科學(xué)院 研究生院,北京 100049)

苯并色烯衍生物具有廣泛的藥理活性和生理活性，如抗發(fā)育不全[1]、抗過敏[2]和抗癌活性[3]等。苯并色烯環(huán)上連有氰基和氨基等取代基的衍生物是合成某些具有特殊結(jié)構(gòu)的天然產(chǎn)物的重要中間體[4,5]。文獻(xiàn)[6～8]方法合成苯并色烯大多是通過Knoevenagel縮合和Michael加成兩步反應(yīng)分步完成的。

本文在前期[9]綠色合成工作的基礎(chǔ)上，以1,4-二氮雜二環(huán)[2.2.2]辛烷(DABCO)為催化劑，水為溶劑，采用“一鍋法”合成了苯并色烯衍生物(2a～2q, Scheme 1),收率26%～95%，其結(jié)構(gòu)經(jīng)1H NMR，13C NMR和MS確認(rèn)。

該方法是一種簡潔、有效的綠色合成方法。避免了使用有機(jī)溶劑造成的環(huán)境污染；“一鍋法”合成目標(biāo)產(chǎn)物可減少分步反應(yīng)的產(chǎn)率損失。

1 實(shí)驗(yàn)部分

1．1 儀器與試劑

Büchi B-545型熔點(diǎn)測定儀;Bruker-300 MHz型核磁共振儀(DMSO-d6為溶劑，TMS為內(nèi)標(biāo));Bruker BIO TOF ⅢQ型高分辨質(zhì)譜儀。

Scheme1

薄層層析硅膠，青島海洋化工廠；其余所用試劑均為分析純。

1.2 合成(以2a為例)

在反應(yīng)管中加入苯甲醛(1a) 64 mg(0.6 mmol),丙二腈46 mg(0.7 mmol)和DABCO 11 mg(0.1 mmol)的水溶液5 mL,攪拌下于室溫反應(yīng)30 min;加入2-羥基-1,4-萘醌 87 mg(0.5 mmol),于100 ℃反應(yīng)至終點(diǎn)(TLC跟蹤)。旋干水后經(jīng)硅膠柱層析[洗脫劑:V(二氯甲烷) ∶V(乙酸乙酯)=20 ∶1]分離得紅褐色固體2a130 mg。

用類似方法合成紅褐色固體2b～2q，其熔點(diǎn)與文獻(xiàn)[10～12]值一致。

2a:1H NMRδ: 4.59(s, 1H), 7.20～7.31(m, 7H), 7.80～7.87(m, 3H), 8.02～8.04(m, 1H);13C NMRδ: 36.6, 57.6, 119.4, 122.1, 125.9, 126.1, 127.2, 127.8, 128.7, 130.6, 131.1, 134.2, 134.6, 143.6, 149.0, 158.4, 176.9, 182.6。

2c:1H NMRδ: 3.78(s, 3H), 4.93(s, 1H), 6.86(t,J=7.2 Hz, 1H), 6.99(d,J=8.1 Hz, 1H), 7.17～7.23(m, 4H), 7.82～7.87(m, 3H), 8.04～8.07(m, 1H);13C NMRδ: 31.2, 55.8, 56.5, 111.7, 119.4, 120.7, 121.9, 125.8, 126.0, 128.4, 129.1, 130.5, 131.0, 131.3, 134.1, 134.6, 149.5, 156.8, 158.9, 177.0, 182.5; HR-ESI-MS: Calcd for C21H14N2O4Na{[M+Na]+} 381.084 6, found 381.084 1。

2d:1H NMRδ: 5.15(s, 1H), 7.23～7.26(m, 2H), 7.34～7.44(m, 4H), 7.84～7.87(m, 3H), 8.05～8.07(m, 1H);13C NMRδ: 33.5, 56.3, 118.8, 121.3, 125.8, 126.1, 127.8, 128.7, 129.4, 130.5, 130.6, 130.9, 132.0, 134.2, 134.6, 140.9, 149.5, 158.4, 176.8, 182.4; HR-ESI-MS: Calcd for C20H11N2O3ClNa{[M+Na]+} 385.035 0, found 385.034 3。

2h:1H NMRδ: 5.15(s, 1H), 7.15～7.60(m, 6H), 7.82～7.84(m, 3H), 8.03～8.05(m, 1H);13C NMRδ: 35.9, 56.5, 118.7, 121.4, 122.7, 125.8, 126.1, 128.4, 128.9, 130.6, 130.9, 132.6, 124.2, 134.6, 142.8, 149.5, 158.3, 176.8, 182.4; HR-ESI-MS: Calcd for C20H11N2O3BrNa{[M+Na]+} 428.984 5, found 428.984 8。

2k:1H NMRδ: 5.39(s, 1H), 7.45～7.48(m, 3H), 7.58～7.67(m, 2H), 7.82～7.84(m, 3H), 7.91～7.93(m, 1H), 8.03～8.05(m, 1H);13C NMRδ: 31.1, 55.9, 118.6, 121.2, 124.0, 125.8, 126.1, 128.4, 130.6, 130.7, 131.3, 133.8, 134.2, 134.6, 137.8, 148.5, 149.0, 158.9, 176.7, 182.6; HR-ESI-MS: Calcd for C20H11N3O5Na{[M+Na]+} 396.059 1, found 396.059 9。

2m:1H NMRδ: 4.65(s, 1H), 7.02～7.07(m, 1H), 7.16～7.19(m, 2H), 7.32～7.37(m, 3H), 7.81～7.89(m, 3H), 8.03～8.06(m, 1H);13C NMRδ: 36.3, 57.1, 113.8, 114.1, 114.4, 114.7, 119.2, 121.1, 123.9, 125.8, 126.1, 130.4, 130.5, 130.8, 131.1, 134.2, 134.5, 146.5, 146.6, 149.3, 158.4, 160.7, 164.0, 176.8, 182.6; HR-ESI-MS: Calcd for C20H11N2O3FNa{[M+Na]+} 369.064 6, found 369.065 2。

2 結(jié)果與討論

2.1 芳醛底物擴(kuò)展

反應(yīng)條件同1.2，擴(kuò)展芳醛底物(2b～2q),實(shí)驗(yàn)結(jié)果見表1。由表1可見，芳環(huán)上有給電子取代基時(shí)，收率較高。芳環(huán)上有吸電子取代基時(shí)，收率相對較低。底物的空間位阻對反應(yīng)的影響也很大，位阻越大，收率越低。

表 1 芳醛底物的擴(kuò)展*

*反應(yīng)條件同1.2

Scheme 2

2.2 DABCO的作用及反應(yīng)機(jī)理

DABCO做為堿，催化Knoevenagel縮合和Michael加成反應(yīng)，經(jīng)環(huán)化異構(gòu)化得到產(chǎn)物2。DABCO在反應(yīng)過程中起到重要作用，推測其反應(yīng)機(jī)理如Scheme 2所示。

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