表 1
优化芳基烯基酮1b和烯丙醇2a的MBH反应a
Table 1.
Optimization of MBH reaction of aryl vinyl ketone 1b with allylic alcohol 2aa
引用本文:
李娅琼, 黄志真. 过渡金属催化和有机小分子参与的α,β-不饱和酮与烯丙醇的Morita-Baylis-Hillman反应[J]. 化学学报,
2017, 75(3): 280-283.
doi:
10.6023/A16110587
Citation: Li Yaqiong, Huang Zhizhen. Morita-Baylis-Hillman Reaction of α,β-Unsaturated Ketones with Allylic Alcohols by the Combination of Transition-Metal Catalysis and Organomediation[J]. Acta Chimica Sinica, 2017, 75(3): 280-283. doi: 10.6023/A16110587
Citation: Li Yaqiong, Huang Zhizhen. Morita-Baylis-Hillman Reaction of α,β-Unsaturated Ketones with Allylic Alcohols by the Combination of Transition-Metal Catalysis and Organomediation[J]. Acta Chimica Sinica, 2017, 75(3): 280-283. doi: 10.6023/A16110587
过渡金属催化和有机小分子参与的α,β-不饱和酮与烯丙醇的Morita-Baylis-Hillman反应
English
Morita-Baylis-Hillman Reaction of α,β-Unsaturated Ketones with Allylic Alcohols by the Combination of Transition-Metal Catalysis and Organomediation
Abstract:
The Morita-Baylis-Hillman (MBH) reaction of α,β-unsaturated carbonyl compounds with allylic halides or allylic esters has been reported. Compared with allylic halides and allylic esters, allylic alcohols are usually more easily prepared. However, to the best of our knowledge, there is no systematic results on the MBH reaction of α,β-unsaturated carbonyl compounds with allylic alcohols. Our experimental results demonstrated that by the catalysis of 10 mol% Pd (PPh3)4 and the mediation of 100 mol% P (n-Bu)3, various aryl vinyl ketones 1a~1g were able to undergo the MBH reaction smoothly with allylic alcohol 2a in the mixed solvents of toluene/(CF3)2CHOH (V/V=35/1) at 60℃ under nitrogen, affording desired α-allylated products 3aa~3ga in the yields of 57%~80%. The MBH reaction is compatible with a series of functional groups on the benzene ring in 1a~1g, such as fluoro, chloro, trifluoromethyl, methyl, and methoxyl group. Naphthyl group instead of benzene group in aryl vinyl ketone 1h also led to α-coupling product 3ha in a good yield. Various 3-aryl allylic alcohols 2b~2f were also able to undergo the MBH reaction smoothly with vinyl ketone 1b, affording the desired α-allylated products 3bb~3bf in good yields with excellent regioselectivities and E-selectivities. 2-Methylprop-2-en-1-ol (2g), 1-phenylprop-2-en-1-ol (2h) or 1, 3-diphenylprop-2-en-1-ol (2i) also performed the MBH reaction expediently with vinyl ketone 1b to give the corresponding α-coupling product 3bg, 3bb, or 3bi. A plausible mechanism using (CF3)2CHOH to both form phosphonium salt 4 and activate allylic alcohols was also proposed. The MBH reaction has many advantages, such as easy availability of starting materials, good tolerance to many functional groups, excellent regioselectivities and E-stereoselectivities, and satisfactory yields. Thus the MBH reaction of aryl vinyl ketones with allylic alcohols may have practical applications in organic synthesis or industry in the future.
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Key words:
- MBH reaction
- / α,β-unsaturated ketone
- / allylic alcohol
- / transition-metal catalysis
- / organomediation
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1 引言
Morita-Baylis-Hillman (MBH) 反应是一类形成碳-碳键的重要反应, 并被广泛用于合成多官能团分子[1].在有机小分子的影响下, 通常在胺或膦的催化下, MBH反应可高效地在活化烯烃的α-位与碳亲电试剂偶联.所用的活化烯烃可以是丙烯醛、烷基烯基酮、丙烯酸酯、丙烯酸酰胺、丙烯腈、烯基砜、烯基磺酸酯、烯基膦酸酯等[1a].所用的碳亲电试剂可以是醛[1a]、1, 2-二酮[1a]、醛亚胺[1a]、环氧化物[2]、氯化三芳基铋[3]等. 2005年Krafft等[4]报道, 在叔膦作用下, 含α, β-不饱和酮和卤代烷结构单元的底物, 可发生分子内MBH反应, 生成含五元或六元环的α, β-不饱和酮.目前, MBH烷基化, 尤其是分子间的MBH烷基化, 仍然具有挑战性.文献报道, 在有机小分子催化或参与下, α, β-不饱和羰基化合物可与烯丙基卤化物发生MBH反应[5]. Krafft等[5a]还报道, 在叔膦作用下, 含α, β-不饱和酮和烯丙醇结构单元的底物, 可发生烯丙醇的氯代和随后的分子内MBH“一锅”反应, 生成含五元或六元环的α, β-不饱和酮. 2016年我们课题组[6a]发现, 在过渡金属催化和有机小分子参与下, 如果有质子酸存在, α, β-不饱和酮可与烯丙基羧酸酯顺利地发生分子间的MBH反应.大多数情况下, 烯丙基卤化物或烯丙基羧酸酯比烯丙醇难制备.然而, 有关α, β-不饱和羰基化合物与烯丙醇的MBH反应的系统性研究, 还未见报道.在此, 我们报道有关过渡金属催化和有机小分子参与的α, β-不饱和酮与烯丙醇的MBH反应.
2 结果和讨论
我们将芳基烯基酮1b和烯丙醇2a作为模板底物, 来探索并优化它们的MBH反应.实验表明, 在氮气氛围中, 在Pd (PPh3)4 (10 mol%) 催化下和P (n-Bu)3 (100 mol%) 参与下, 如果在60 ℃温度下单一地用甲苯或CF3CH2OH作溶剂[7], 没有得到所需的α-烯丙基化产物3ba(表 1, Entries 1~2).然而, 当使用甲苯和CF3CH2OH的混合溶剂, 得到了所需的α-烯丙基化产物3ba, 但产率较低 (表 1, Entry 3).用各种醇与甲苯作混合溶剂后发现, 更易解离出质子的 (CF3)2CHOH (HFIP)[8]与甲苯的混合溶剂, 效果最好, 可以较好的产率得到α-烯丙基化产物3ba(表 1, Entry 5;以及SI).同时, 也筛选了其它钯催化剂、叔膦和叔胺, 均未获得更好的产率 (表 1, Entries 7~12 vs. Entry 5).用其它有机溶剂与HFIP混合, 得不到或得到低产率的α-烯丙基化产物3ba(表 1, Entries 13~14 vs. Entry 5;以及SI). P (n-Bu)3的使用量降至50 mol%时, 3ba的产率大幅度降至31%(表 1, Entry 5).单一使用Pd (PPh3)4或P (n-Bu)3时, 不能得到3ba.因此, 该MBH反应的优化条件可概括为: 10 mol% Pd (PPh3)4, 100 mol% P (n-Bu)3, 甲苯/(CF3)2CHOH (V/V＝35/1) 作溶剂, 60 ℃反应温度, 氮气保护.
表 1
优化芳基烯基酮1b和烯丙醇2a的MBH反应a
Table 1.
Optimization of MBH reaction of aryl vinyl ketone 1b with allylic alcohol 2aa
Entry [Pd] Phosphine or Amine Solvent (V/V) Yieldb/% 1 Pd (PPh3)4 P (n-Bu)3 toluene 0 2 Pd (PPh3)4 P (n-Bu)3 CF3CH2OH 0 3 Pd (PPh3)4 P (n-Bu)3 toluene/CF3CH2OH (15/1) 18 4 Pd (PPh3)4 P (n-Bu)3 toluene/HFIP (15/1) 31 5 Pd (PPh3)4 P (n-Bu)3 toluene/HFIP (35/1) 75 (31c) 6 Pd (PPh3)4 P (n-Bu)3 toluene/HFIP (60/1) 66 7 Pd2(dba)3 P (n-Bu)3 toluene/HFIP (35/1) 53 8 Pd (OAc)2 P (n-Bu)3 toluene/HFIP (35/1) 71 9 Pd (TFA)2 P (n-Bu)3 toluene/HFIP (35/1) 65 10 Pd (PPh3)4 P (Me)3 toluene/HFIP (35/1) 54 11 Pd (PPh3)4 PPh3 toluene/HFIP (35/1) 0 12 Pd (PPh3)4 NEt3 toluene/HFIP (35/1) 0 13 Pd (PPh3)4 P (n-Bu)3 dioxane/HFIP (35/1) 38 14 Pd (PPh3)4 P (n-Bu)3 DME/HFIP (35/1) 0 aThe mixture of 1b (0.10 mmol), 2a (0.30 mmol), catalyst (10 mol%), and phosphine (100 mol%) was stirred in solvent (1.5 mL) at 60 ℃ under N2 for 24 h.bIsolated yields. c50 mol% P (n-Bu)3. 表 1 优化芳基烯基酮1b和烯丙醇2a的MBH反应a
Table 1. Optimization of MBH reaction of aryl vinyl ketone 1b with allylic alcohol 2aa反应物普适性实验表明, 在优化条件下, 各种含推电子基或吸电子基芳基烯基酮1a~1g均能与烯丙醇2a顺利地进行MBH反应, 以57%~80%的产率得到所需的α-烯丙基化产物3aa~3ga(表 2, Entries 1~7).该MBH反应与芳基烯基酮1a~1g中的各种官能团均兼容, 例如:氟、氯、三氟甲基和甲氧基.然而, 用4-硝基苯基烯基酮不能得到所需的α-烯丙基化产物.萘基烯基酮1h可与烯丙醇2a发生MBH反应, 以良好的产率得到α-偶联产物3ha(表 2, Entry 8).各种3-芳基烯丙醇2b~2f均能与芳基烯基酮1b反应, 以较好的产率得到α-烯丙基化产物3bb~3bf.该3-芳基烯丙醇2b~2f发生的MBH反应, 还具有很好的区域选择性和立体选择性, 没有得到相关的异构体 (表 2, Entries 9~13). 2-甲基丙烯-1-醇2g也能与芳基烯基酮1b顺利反应生成相应的α-偶联产物3bg(表 2, Entry 14).带支链的烯丙醇2h可与芳基烯基酮1b反应, 以优秀的区域选择性得到直链的α-烯丙基化产物3bh, 该产物等同于用直链的烯丙醇2b反应所得的产物 (表 2, Entry 15).用1, 3-二苯基烯丙醇2i与芳基烯基酮1b反应, 也能以较好的产率和优秀的E型-立体选择性得到所需的α-烯丙基化产物3bi(表 2, Entry 16).
表 2
过渡金属催化和有机小分子参与的芳基烯基酮1和烯丙醇2的MBH反应a
Table 2.
The MBH reaction of aryl vinyl ketones 1 with allylic alcohols 2 by the combination of transition-metal catalysis and organomediationa
Entry Ar R Product Yieldb/% 1 4-MeOC6H41a H 2a 3aa 57 2 4-MeC6H41b H 2a 3ba 75 3 3-MeC6H4 1c H 2a 3ca 69 4 Ph 1d H 2a 3da 80 5 4-FC6H4 1e H 2a 3ea 73 6 4-ClC6H4 1f H 2a 3fa 64 7 4-CF3C6H4 1g H 2a 3ga 76 8 2-naphthyl 1h H 2a 3ha 82 9 4-MeC6H4 1b C6H5 2b 3bb 68 10 4-MeC6H4 1b 4-MeOC6H4 2c 3bc 77 11 4-MeC6H4 1b 2-MeOC6H4 2d 3bd 63 12 4-MeC6H41b 4-FC6H4 2e 3be 71 13 4-MeC6H4 1b 4-ClC6H4 2f 3bf 65 14c 4-MeC6H4 1b 
3bg 40 15 4-MeC6H4 1b 
3bh 82 16 4-MeC6H4 1b 
3bi 74 a The mixture of 1 (0.10 mmol), 2 (0.30 mmol), Pd (PPh3)4 (10 mol%), P (n-Bu)3 (100 mol%) was stirred in toluene/(CF3)2CHOH (V/V＝35/1, 1.5 mL) at 60 ℃ under N2 for 24 h.bIsolated yields. c toluene/(CF3)2CHOH (V/V＝25/1, 1.5 mL) at 80 ℃. 表 2 过渡金属催化和有机小分子参与的芳基烯基酮1和烯丙醇2的MBH反应a
Table 2. The MBH reaction of aryl vinyl ketones 1 with allylic alcohols 2 by the combination of transition-metal catalysis and organomediationa如所用的α, β-不饱和酮为烷基烯基酮1i, 在优化条件下, 也能与烯丙醇2b进行MBH反应, 生成α-烯丙基化产物3ib.但产率相比较用芳基烯基酮1b, 有显著降低 (图式1, Eq. 1 vs. 表 2, Entry 9).当使用β-位有取代基的芳基烯基酮1j, 需将温度提高至105 ℃, 才能与烯丙醇2a发生MBH反应, 生成α-偶联产物3ja(图式1, Eq. 2).
图 图式1
扩展的α, β-不饱和酮1i~1j的MBH反应
Figure 图式1.
The MBH reactions of expanded scope of α, β-unsaturated ketones 1i~1j
在参考以往MBH反应和π-烯丙基钯的文献基础上[1a, 9], 我们提出了如下可能的反应机理 (图式2).首先, P (n-Bu)3亲核加成到芳基烯基酮1上, 得到的膦中间体随即从六氟异丙醇 (HFIP) 获得质子, 从而生成鏻盐4.鏻盐4的形成旨在减少Rauhut-Currier副产物[6a].然后, 鏻盐4上的质子被六氟异丙氧基负离子缓慢夺走, 形成活性膦中间体5.此时, 被HFIP活化的烯丙醇[7]与钯 (0) 催化剂发生氧化加成, 形成π-烯丙基钯络合物6.膦中间体5亲核进攻钯络合物6, 生成鏻盐7; 同时产生的钯 (0) 催化剂可继续循环催化.最后, 鏻盐7发生β-氢消除生成α-烯丙基化产物3, 同时产生P (n-Bu)3.
图 图式2
芳基烯基酮1和烯丙醇2的MBH反应的可能机理
Figure 图式2.
Possible mechanism for the MBH reaction of aryl vinyl ketone 1 with allylic alcohol 2
3 结论
综上所述, 我们利用Pd (PPh3)4催化和P (n-Bu)3参与, 在toluene/(CF3)2CHOH混合溶剂中, 开发出一种新颖的α, β-不饱和酮1和烯丙醇2的MBH反应, 以较好的产率得到α-烯丙基化产物3.并提出了利用 (CF3)2CHOH生成鏻盐和活化烯丙醇的可能机理.该MBH反应具有原料易制备、官能团兼容性好、优秀的区域选择性和立体选择性、较好的产率等诸多优点, 使得该反应未来有可能被应用于有机合成或化工生产中.
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[1]
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(a) Krafft, M. E.; Wright, J. A. Chem. Commun. 2006, 2977; (b) Cran, J. W.; Krafft, M. E.; Seibert, K. A.; Haxell, T. F. N.; Wright, J. A.; Hirosawa, C.; Abboud, K. A. Tetrahedron 2011, 67, 9922.
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Koech, P. K.; Krische, M. J. J. Am. Chem. Soc. 2004, 126, 5350. doi: 10.1021/ja048987i
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Krafft, M. E.; Seibert, K. A.; Haxell, T. F. N.; Hirosawa, C. Chem. Commun. 2005, 5772.
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(a) Krafft, M. E.; Haxell, T. F. N. J. Am. Chem. Soc. 2005, 127, 10168; (b) Villar, I. S.; Gradillas, A.; Domínguez, G.; Pérez-Castells, J. Org. Lett. 2010, 12, 2418; (c) Gradillas, A.; Belmonte, E.; Silva, R. F.; Pérez-Castells, J. Eur. J. Org. Chem. 2014, 9, 1935; (d) Basavaiah, D.; Sharada, D. S.; Kumaragurubaran, N.; Reddy, R. M. J. Org. Chem. 2002, 67, 7135.
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[8]
The pKa value of (CF3)2CHOH is 9.3. For details, see: Fedotova, A.; Crousse, B.; Chataigner, I.; Maddaluno, J.; Rulev, A. Y.; Legros, J. J. Org. Chem. 2015, 80, 10375.
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[1]
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图式1 扩展的α, β-不饱和酮1i~1j的MBH反应
Scheme 1 The MBH reactions of expanded scope of α, β-unsaturated ketones 1i~1j
图式2 芳基烯基酮1和烯丙醇2的MBH反应的可能机理
Scheme 2 Possible mechanism for the MBH reaction of aryl vinyl ketone 1 with allylic alcohol 2
表 1 优化芳基烯基酮1b和烯丙醇2a的MBH反应a
Table 1. Optimization of MBH reaction of aryl vinyl ketone 1b with allylic alcohol 2aa
Entry [Pd] Phosphine or Amine Solvent (V/V) Yieldb/% 1 Pd (PPh3)4 P (n-Bu)3 toluene 0 2 Pd (PPh3)4 P (n-Bu)3 CF3CH2OH 0 3 Pd (PPh3)4 P (n-Bu)3 toluene/CF3CH2OH (15/1) 18 4 Pd (PPh3)4 P (n-Bu)3 toluene/HFIP (15/1) 31 5 Pd (PPh3)4 P (n-Bu)3 toluene/HFIP (35/1) 75 (31c) 6 Pd (PPh3)4 P (n-Bu)3 toluene/HFIP (60/1) 66 7 Pd2(dba)3 P (n-Bu)3 toluene/HFIP (35/1) 53 8 Pd (OAc)2 P (n-Bu)3 toluene/HFIP (35/1) 71 9 Pd (TFA)2 P (n-Bu)3 toluene/HFIP (35/1) 65 10 Pd (PPh3)4 P (Me)3 toluene/HFIP (35/1) 54 11 Pd (PPh3)4 PPh3 toluene/HFIP (35/1) 0 12 Pd (PPh3)4 NEt3 toluene/HFIP (35/1) 0 13 Pd (PPh3)4 P (n-Bu)3 dioxane/HFIP (35/1) 38 14 Pd (PPh3)4 P (n-Bu)3 DME/HFIP (35/1) 0 aThe mixture of 1b (0.10 mmol), 2a (0.30 mmol), catalyst (10 mol%), and phosphine (100 mol%) was stirred in solvent (1.5 mL) at 60 ℃ under N2 for 24 h.bIsolated yields. c50 mol% P (n-Bu)3. 
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表 2 过渡金属催化和有机小分子参与的芳基烯基酮1和烯丙醇2的MBH反应a
Table 2. The MBH reaction of aryl vinyl ketones 1 with allylic alcohols 2 by the combination of transition-metal catalysis and organomediationa
Entry Ar R Product Yieldb/% 1 4-MeOC6H41a H 2a 3aa 57 2 4-MeC6H41b H 2a 3ba 75 3 3-MeC6H4 1c H 2a 3ca 69 4 Ph 1d H 2a 3da 80 5 4-FC6H4 1e H 2a 3ea 73 6 4-ClC6H4 1f H 2a 3fa 64 7 4-CF3C6H4 1g H 2a 3ga 76 8 2-naphthyl 1h H 2a 3ha 82 9 4-MeC6H4 1b C6H5 2b 3bb 68 10 4-MeC6H4 1b 4-MeOC6H4 2c 3bc 77 11 4-MeC6H4 1b 2-MeOC6H4 2d 3bd 63 12 4-MeC6H41b 4-FC6H4 2e 3be 71 13 4-MeC6H4 1b 4-ClC6H4 2f 3bf 65 14c 4-MeC6H4 1b 3bg 40 15 4-MeC6H4 1b 3bh 82 16 4-MeC6H4 1b 3bi 74 a The mixture of 1 (0.10 mmol), 2 (0.30 mmol), Pd (PPh3)4 (10 mol%), P (n-Bu)3 (100 mol%) was stirred in toluene/(CF3)2CHOH (V/V＝35/1, 1.5 mL) at 60 ℃ under N2 for 24 h.bIsolated yields. c toluene/(CF3)2CHOH (V/V＝25/1, 1.5 mL) at 80 ℃.
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