钯催化烯丙基碳酸肟脱羧合成烯丙基肟
Palladium-Catalyzed Allyl Oxime from Allyloxycarbonyl Oxime
DOI: 10.12677/JOCR.2015.31012, PDF, HTML, XML,    科研立项经费支持
作者: 蔡 波, 李文广, 皮少锋, 孙汉州：中南林业科技大学应用化学研究所，湖南 长沙
关键词: 钯；脱羧；烯丙基肟；Palladium； Decarboxylation； Allyl Oxime
摘要: 肟类化合物是一类重要的含氮化合物，广泛存在于天然产物、药物和活性物质的一种单元结构，是一种重要的有机合成中间体。研究了在钯催化条件下烯丙基碳酸肟脱羧反应，发展了一种反应条件温和，原料便宜易得，对环境友好的合成烯丙基肟方法，在常温下，以Pd(PPh3)4为催化剂，DCM为溶剂的反应体系中，反应8分钟就可以得到较高收率的烯丙基肟。并对该反应可能的机理进行了探讨。
Abstract: Oximes, which are important classes of nitrogen compounds, are ubiquitous in natural products, drugs as well as materials, and are important intermediates in organic synthesis. We have devel-oped a mild and convenient protocol for the synthesis of allyl oximes. In the presence of Pd(PPh3)4 and DCM, allyloxycarbonyl oximes successfully underwent decaboxylate reaction at room tem-perature to afford the corresponding allyl oximes in moderate good yields in eight minutes. And the possible mechanism of the reaction was discussed.
文章引用：蔡波, 李文广, 皮少锋, 孙汉州. 钯催化烯丙基碳酸肟脱羧合成烯丙基肟[J]. 有机化学研究, 2015, 3(1): 84-89. http://dx.doi.org/10.12677/JOCR.2015.31012

1. 引言

钯催化脱羧反应是构建C-C键，C-X键的高效合成手段[1] [2] ，这类反应可以避免经典偶联反应中常用的强酸、强碱和有毒的金属有机试剂，副产物只有二氧化碳，没有对环境不友好卤化物的生成[3] -[5] ，并且反应条件温和，原料易得，肟类化合物是广泛存在于天然产物和活性物质的一种单元结构，具有广谱的杀菌消炎作用[6] 。所以经常利用肟来修饰一些药物，一些广泛使用的药物如头孢唑肟钠，头孢噻肟钠，头孢特仑酯，头孢克肟等胺噻肟类头孢菌素[7] [8] 。目前，实验室通常使用醛肟或酮肟在强碱性条件下和烯丙基卤反应合成烯丙基肟，或者用烯丙基醇胺和醛反应合成烯丙基肟[9] [10] 。这两种方法虽然非常成熟，并应用于工业生产中，但需要在强碱性条件下才能反应，其他基团对碱性的耐受性抑制这种方法在药物合成中的应用[11] -[14] 。

2. 实验部分

2.1. 仪器与试剂

本实验所用的溶剂和试剂均为分析纯，购自国药集团化学试剂有限公司百灵威、Acros、Tci等公司，未进一步处理，层析柱使用300~400目硅胶。核磁共振氢、碳谱采用Bruker AV 500型核磁共振仪，TMS(四甲基硅烷)为内标，CDCl3 (氘代氯仿)为溶剂；气质由岛津GC/MS QP2010 PLUS测定。

2.2. 实验方法

干燥的 Schlenk 管中加入烯丙基碳酸肟酯(0.2 mmol)，Pd(PPh3)4 (5 % mol)，DCM (二氯甲烷，2 mL)，Ar保护，常温下反应8 min，反应结束后，加入乙醚，转移至圆底烧瓶，旋转蒸发仪蒸干溶剂，得到粘稠液体，以300~400目硅胶为固定相，以石油醚/乙酸乙酯为流动相分离提纯得到目标产物。

2.3. 产物结构表征

Benzaldehyde O-cinnamyloxime (2a)

黄色油状液体, 1HNMR (500 MHz, CDCl3) δ: 8.14(s, 1H), 7.60 -7 .59 (m, 2H), 7.42 - 7.36 (m, 5H), 7.32 (t, J = 7.5 Hz, 2H), 7.24 (t, J = 7.5 Hz, 1H), 6.69 (dd, J = 15.5 Hz, 1H), 6.45 - 6.40 (m, 1H), 4.85 - 4.83 (m, 1H); 13CNMR (125 MHz, CDCl3) δ: 148.9, 136.6, 133.5, 132.2, 129.8, 128.5, 127.8, 127.1, 126.6, 125.1; (EI, 70 eV) m/z (%): 161 (M+, 49), 131 (35), 117 (22), 77 (77), 41 (100).

Acetophenone O-allyl oxime (2b)

无色油状液体, 1HNMR (500 MHz, CDCl3) δ: 7.65 - 7.64 (m, J = 7.5 Hz, 1H), 7.36 - 7.35 (m, 3H), 6.11 - 6.03 (m, 1H), 5.36 (dd, J = 1.5 Hz 1H), 5.33 (t, J = 5 Hz, 1H), 4.71 (d, J = 5.5 Hz, 1H), 5.44 (d, J = 1.5 Hz, 1H), 2.61 (s, 3H); 13CNMR (125 MHz, CDCl3 δ: 154.8, 136.7, 134.5, 129.0, 128.4, 126.0, 117.3, 75.0, 12.8; LRMS (EI, 70 eV) m/z (%): 174 (M+, 100), 103 (20), 77 (73).

3,4-dihydro-1(2H)-one O-allyl oxime (2c)

无色油状液体, 1HNMR (500 MHz, CDCl3) δ: 7.70 (d, J = 8.0 Hz, 1H), 7.33 - 7.26 (m, H), 7.24 - 7.22 (m, 2H), 6.10 - 6.03 (m, 1H), 5.37 - 5.36 (m, 1H), 5.33 - 5.22 (m, 1H), 4.70 - 4.68 (m, 2H), 3.05 - 2.93 (m, 2H), 2.92 - 2.91 (m, 2H); 13CNMR (125 MHz, CDCl3) δ: 162.9, 148.2, 136.1, 134.6, 130.2, 126.9, 125.5, 121.6, 117.2, 75.0, 28.6, 26.5; LRMS (EI, 70 eV) m/z (%): 201 (M+, 100), 184 (35), 129 (43), 41 (100).

3,4-dihydronaphthalen-1(2H)-one-O-allyl oxime (2d)

无色油状液体, 1HNMR (500 MHz, CDCl3) δ: 7.97 (d, J = 7.5, 1H), 7.25 - 7.11 (m, 3H), 6.10 - 6.03 (m, 1H), 5.35 (dd, J = 1.5, 1H), 5.32 - 5.21 (m, 1H), 4.70-4.69 (m, 2H), 2.78 - 2.72 (m, 4H), 1.87 - 182 (2H); 13CNMR (125 MHz, CDCl3) δ: 154.2, 139.5, 134.6, 130.7, 128.9, 128.5, 126.3, 124.2, 117.2, 75.1, 29.7, 24.4, 21.4; LRMS (EI, 70 eV) m/z (%): 201 (M+, 59), 184 (35), 129 (43), 41 (100).

Benzaldehyde O-allyl oxime (2e)

无色油状液体, 1HNMR (500 MHz, CDCl3) δ: 8.12 (s, 1H), 7.59 - 7.57 (m, 2H), 7.36 (t, J = 3.5 Hz, 3H), 6.10 - 6.01 (m, 1H), 5.34 (d, J = 15.5 Hz, 1H), 5.25 (d, J = 9.0 Hz, 1H), 4.67 (d, J = 4.5 Hz, 2H); 13CNMR (125 MHz, CDCl3) δ: 148.8, 134.0, 132.2, 129.8, 128.6, 127.0, 117.9, 75.1.LRMS (EI, 70 eV) m/z (%): 161 (M+, 50), 131 (35), 91 (39), 41 (100).

3-methoxybenzaldehyde O-allyl oxime (2f)

无色油状液体, 1HNMR (500 MHz, CDCl3) δ: 8.08 (s, 1H), 7.29-7.25 (m, 1H), 7.16 (d, J = 2.5 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.93-6.91 (m, 1H), 6.09-6.01 (m, 1H), 5.37 (t, J = 1.5, 1H), 5.34-5.24 (m, 1H), 4.68 (t, J = 4.5 Hz, 2H ), 3.83 (s, 3H); 13CNMR (125 MHz,CDCl3) δ: 159.8, 148.8, 133.9, 133.5, 129.7, 120.1, 118.0, 116.2, 111.1, 75.2, 55.3; LRMS (EI, 70 eV) m/z (%): 191(M+, 48), 131 (56), 91 (48), 41 (100).

4-methoxybenzaldehyde O-allyl oxime (2g)

无色油状液体, 1H NMR (500 MHz, CDCl3) δ: 8.07 (s, 1H), 7.52 (t, J = 7, 2H), 6,89 (d, J = 8.5, 2H), 6.09-6.01 (m, 1H), 5.36 (d, J = 2.0, 1H), 5.33 (d, J = 1.5, 1H), 4.65 (d, J = 5.5, 2H), 3.82 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 160.9, 148.5, 134.1, 128.5, 124.8, 117.8, 114.1, 75.0, 55.3, 29.7; LRMS (EI, 70 eV) m/z (%): 191(M+, 73), 134 (19), 77 (56), 41 (100).

4-chlorobenzaldehyde O-allyl oxime (2h)

无色油状液体, 1HNMR (500 MHz, CDCl3) δ: 8.07 (s, 1H), 7.51 (d, J = 8.5, 2H), 7.33 (d, J = 9.0, 2H), 6.08-6.00 (m, 1H), 5.37 (d, J = 1.5, 1H), 5.33 (d, J = 1.5, 1H), 4.67 (d, J = 5.5, 2H); 13CNMR (125 MHz, CDCl3) δ: 147.6, 135.6, 133.8, 130.7, 128.9, 128.2, 118.1, 75.3; LRMS (EI, 70 eV) m/z (%): 195 (M+, 35), 165 (14), 111 (26), 41 (100).

benzaldehyde O-3-methylbut-2-enyl oxime (2i)

无色油状液体, 1HNMR (500 MHz, CDCl3) δ: 8.33 (s, 1H), 7.72 (t, J = 1.5, 2H), 7.48 - 7.43 (m, 1H), 7.14 (t, J = 7.5, 2H), 5.46 - 5.43 (m, 1H), 4.78 (d, J = 7.5, 2H), 1.78 (s, 3H), 1,76 (s, 3H); 13CNMR (125 MHz, CDCl3) δ: 155.6, 153.7, 140.9, 131.6, 129.8, 128.8, 128.3, 117.5, 69.3, 25.7, 18.0; LRMS (EI, 70 eV) m/z (%): 18 9(M+, 52), 147 (23), 120 (57), 41 (100).

benzaldehyde O-2-methylallyl oxime (2j)

无色油状液体, 1HNMR (500 MHz, CDCl3) δ: 8.37 (s, 1H), 7.71 (t, J = 6.5, 2H), 7.45 - 7.39 (m, 3H), 4.85 (s, 1H), 4.80 (s, 1H), 4.39 (t, J = 7.0, 2H), 2.45 (t, J = 7.0, 2H), 1.79 (s, 3H); 13CNMR (125 MHz, CDCl3) δ: 155.6, 153.6, 140.7, 131.6, 129.7, 128.7, 128.2, 112.7, 66.6, 36.5, 22.3; LRMS (EI, 70 eV) m/z (%): 175(M+, 34), 161 (47), 120 (59), 41 (100).

3. 结果与讨论

3.1. 钯催化烯丙基碳酸肟脱羧反应条件优化

以苯甲醛肟碳酸肉桂酯为模板，对钯催化剂、溶剂和反应温度进行筛选，探索反应最佳条件(如表1所示)。首先以零价Pd(PPh3)4为催化剂，考察各种溶剂对反应的影响，在一系列溶剂中都能得到中等收率，在PhMe和DME的反应体系中产率分别为76%和69% (表1，Entry 1和2)，THF，MeCN和DMSO为溶剂时产率稍有降低，以DCM为溶剂时反应8 min，产率达到88% (表1，Entry 5)，值得一提的是在水中该反应也能达到47%的收率，以水为溶剂经济价值和环保效益都是最理想的，遗憾的是产率太低。接下来我们以DCM为溶剂考察钯催化剂对反应的影响，分别尝试了Pd(dba)2，Pd(dppf)Cl2，Pd(OAc)2，PdCl2/PPh3和Pd(PPh3)Cl2，发现二价钯催化剂得到较高收率，但比零价Pd(PPh3)4产率低(表1，Entry 8 - 13)。同时还考察了温度对反应的影响，发现升高温度到40℃时产率变化不大，当温度升到80℃时，原料分解副产物增加，产率反而降低(表1，Entry 15)。但当温度降至0℃时，反应45分钟，产率只有60%。因此，我们发现该反应的最佳条件：在常温下以Pd(PPh3)4为催化剂，DCM为溶剂，反应8分钟产率达到88%。

3.2. 烯丙基碳酸肟脱羧反应适应性研究

在最佳反应条件下，对一系列的烯丙基碳酸肟脱羧反应进行研究(如表2所示)，该反应条件对酮肟的适应性较好，其中苯乙酮肟脱羧的产率达到90% (Entry 2)，环酮肟脱羧反应产率也较高，但2,3-二氢-1-茚酮肟的产率只有74% (Entry 3)，当醛肟苯环上带有不同的取代基团时，对产率的影响较小(Entry 6 - 8)，当带有较弱的吸电子基时产率几乎不受影响(Entry 8)。并且在该反应条件下末端烯烃和中间烯烃都能得到较高的收率(9 - 10)。

3.3. 钯催化烯丙基碳酸肟脱羧反应可能机理

基于实验结果和相关文献报道[15] ，探讨了钯催化烯丙基碳酸肟酯脱羧合成烯丙基肟的可能机理，零价钯和反应物1加成生成Pd-π-烯丙基金属物种A，A随后脱去二氧化碳，生产金属物种B，中间体B还原消除可能存在两条途径，生成产物2或3，但实验结果显示只有产物2，这可能是因为中间烯烃比末端烯烃的稳定性要好，从而得到单一产物。

Table 1. Reaction conditions optimization

表1. 反应条件优化a

aReaction conditions: 1a (0.2 mmol), catalyst (5 mol %) in solvent (2 mL) at room temperature; bIsolated yield; c,d10 mol % PPh3 was used.

Table 2. Palladium-catalyzed allyl oxime from allyloxycarbonyl oxime

表2. 钯催化烯丙基碳酸肟脱羧合成烯丙基肟a

aReaction conditions: 1a (0.2 mmol), Pd(PPh3)4 (5 mol %) in solvent (2 mL) at room temperature; bIsolated yield.

4. 结论

我们发展了一种新型的快速合成烯丙基肟的方法，在常温下以Pd(PPh3)4为催化剂，DCM为溶剂的反应体系中，反应8分钟就可以得到较高收率的烯丙基肟。该反应条件温和，对环境友好，反应底物适应范围广，反应速度快，为烯丙基肟的合成提供了一种经济、高效的途径。

基金项目

湖南省研究生科研创新基金(CX2013B344)，中南林业科技大学研究生科技创新基金(CX2013B16)。

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