有机合成反应Heck反应

1、经典化学合成反应标准操作 1. 前言1 2. 分子内的 Heck 反应2 2.1生成烯基取代的反应2 2.1.1分子内Heck反应化生成环外双键示例 3 2.2形成季碳中心的反应4 2.2.1 分子内不对称Heck 反应示例 5 2.3多烯大环的合成5 2.2.1 Heck反应用于合成大环多烯示例6 3. 分子间的Heck反应7 3.1 常规分子间 Heck 反应7 3.1.1 Pd(OAc)2-P(o-tol)3体系用于不饱和羧酸酯的Heck反应标准操作三.8 3.1.2 不饱和酮的Heck反应标准操作 9 3.1.3杂环芳香卤代物和不饱和羧酸酯的Heck反应标准操作一 9 3.1.4杂环芳

2、香卤代物和不饱和羧酸酯的Heck反应标准操作二 9 3.1.5芳香卤代物和不饱和羧酸的 Heck反应合成反式3-芳基不饱和酸示例.10 3.1.6非共轭双键Heck反应示例 10 3.2不对称分子间 Heck反应11 3.3 非常用离去基团的Heck 反应(Irina P. Beletskaya Chem. Rev. 2000, 100, 3009-3066) 11 3.3.1重氮盐参与的 Heck反应示例 12 3.3.2 酰氯参与的 Heck反应示例 14 1. 刖言 通常把在碱性条件下钯催化的芳基或乙烯基卤代物和活性烯烃之间的偶联反应称 为Heck反应。自从20世纪60年代末Heck和M

3、orizoki独立发现该反应以来，通过对催 化剂和反应条件的不断改进使其的应用范围越来越广泛，使该反应已经成为构成C-C键 的重要反应之一。另外，Heck反应具有很好的Trans选择性 Pd(0) R _x R Z Z X = I, Br, OTf, etc Z = H, R, Ar, CN, CO2R, OR, OAc, NHAc, etc 研究表明，Heck反应的机理有一定的规律，通常认为反应共分四步：(a)氧化加 成(Oxidative addition): RX (R 为烯基或芳基，X=I TfO Br Cl)与 PdL2 的加成， 形成Pd配合物中间体；(b)配位插入 (Cordin

4、ation-insertion):烯键插入Pd-R键的过 程；(c)阳的消除; (d)催化剂的再生：加碱催化使重新得到 PdL2 Pjd - PPh3 oxidative addition ox PPh. Pd-Br PJ-airte rmediate 0 rh3P n complex insertion 总的说来，Heck反应可以分为两大类：分子内反应和分子间反应。第一篇该反应 的报道是Heck在1972年发表 Pd(OAc) 2 (20 mol%) nBu 3N (1 eq) NMP, 100 C, 2h Nolley, J.P.; Heck, R. F.;Tetrahedron 1972

5、, 37, 2320 Pd(OAc) 2 (2 mol%) PPh3, DMF TMEDA (2 equaiv) 125C,5h Ac 43% Indole product formed as result of Pd-H isomerization of product clefin Mori和Ban于1977年首次报道了分子内的 Heck反应: Page 16 of 15 Mori, M.; Ban, K.; Tetrahedro n 1977, 12, 1037 经过三十多年的发展, 不同由可以分成几类。 Heck反应的应用也越来越广泛。每一类反应根据其特点的 2. 分子内的Heck反应

6、 2.1生成烯基取代的反应 该类反应主要用于生成环外双键。环外双键是合成上一大难题，该反应成功的应用 具有重大意义。目前已有合成的报道。 OMe/ OMe 1 A 厂1 .OMe Pd(PPh 3)4 (cat) NEt3 (12 eq) 、OMe MeO Nf 丄NCO2Me MeCN, 80 C, 10h MeO NCO2Me O O 90% Dan ishefsky, S. J.J. Am. Chem. Soc1993, 115, 6094 该反应还被Danishefsky应用到全合成Taxol上。 O Pd(PPh 3)4 (1.1 eq) K2CO3, MeCN, 85 C O 49

7、% Dani shefsky, S. J. J. Am. Chem. Soc1996, 118, 2843 2.1.1分子内Heck反应化生成环外双键示例 MeCN, 80 C , 10h Pd(PPh 3)4 , NEt3(12eq) 1 2 A stirred solution of 1 (98 mg, 0.19 mmol), triethylmine (0.32 mL, 2.3 mmol) and catalytic tetrakis(triphe ny Iphosphi ne)palladium(O) (ca. 5 mg, 4 gol) in 2.4 mL of acet on itr

8、ile was heated at 80 C in a sealed tube under an argon atmosphere for 10 h. The reaction mixture turned dark orange after ca. 10 min, and the catalyst plated out on the walls of the tube as a shiny layer of palladium metal upon completion of the reaction. The reaction mixture was cooled to room temp

9、erature; the react ion was que nched with aqueous NaHCO3(15 mL), and the mixture was extracted with EtOAc (4X 10 mL). The organic extracts were washed with aqueous NaHSO(1 x 15 mL), water (1 x 15 mL), and brine (1 x 15 mL) and dried over MgSO4. Filtration, concentration, and purification of the oran

10、ge residue by flash colu mn chromatography (45:55 EO/hexa nes) gave 66 mg (90%) of 19 as a colorless solid: mp 193-194 C ; Rf = 0.29 (8:2 Et2O/hexanes). 2.2形成季碳中心的反应 从20世纪80年代早期研究以来得到了广泛的应用。1989年，Shibasaki和Overman 首先报道不对称Heck反应。 Pd(OAc)2 (3 mol%) (R)-BINAP (9 mol%) cyclohexe ne (6 mol%) Ag2CO3 (2 eq

11、) NMP, 60 C CO 2Me H 74% (46% ee) J.Org.Chem.1989, 54, 4738 同一年，Overman及其工作组首先利用Heck反应合成了手性季碳原子。 Pd(OAc) 2 (10 mol%) (R,R)-DIOP (10 mol%) Et3N, C 6H6, rt 90% (45% ee) J.Org.Chem. 1989,54,5846 像天然产物physostigmine的合成，成功的运用和Heck反应构成手性的季碳中心。 Pd2(dba) 3-CHCI3 (10 mol%) (S)-BINAP (23 mol%) PMP, DMA, 100 C

12、3 M HCl THF, rt LiAIH4, THF, reflux (88%) MeNH3Cl, Et3N 1) BBr 3, CH 2CI2, rt 2) Na, Et 2O, MeNCO (31%) (-)-physostigm ine Matsuura, T.; Overma n, L.E. J.Am.Chem.Soc.1998, 120, 6500 2.2.1分子内不对称Heck反应示例 MeO 1 10 % Pd 2(dba) 3, 23 % -BINAP, CHCI 3 1,2,2,6,6-pe ntamethylpiperidi ne, DMA, 100C OTIPS 2 A

13、 mixture of Pd 2(dba)3 CHCI 3 (360 mg, 0.347 mol), (s)-BINAP (504 mg, 0.809 mol), and N,N-dimethylacetamide (DMA, 21 mL) was stirred at room temperature for 65 min. To the resulting orange solution was added a solution of compound 1 (1.82 g, 3.51 mol), 1,2,2,6,6-pentamethylpiperidine (3.2 mL, 18 mmo

14、l), and DMA (18 mL), and the reaction was heated at 100 C for 90 min. The result dark solution was poured into half-saturated aqueous NaHCO3 (100 mL) and extracted with ether (3 x 150 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4), and concentrated, and the residue

15、 was purified by sgc (9:1 f 1:1 hexa ne-EtOAc) to give oxin dole eno xysila ne compo und2 (1.29 g, 94%) as a 98:2 mixture of geometric isomers: )25d 1o (c 0.61 C6H6). 2.3多烯大环的合成 分子内Heck反应形成的多烯大环化合物 (大于 13)。Zeigler 就利用Heck反应成 功合成十六元环的大环多烯化合物 O PdCl 2(MeCN) 2 (100 mol%) NEt3, MeCN, 25 C O 55% 16 membe

16、r ring formation Zeigler, F. Tetrahedron, 1981,37, 4035 也有多烯经过多次分子内Heck反应，一步构建多个碳碳键和多元环。 Overma n 就 成功应用Heck反应一步构建了二个环和二个季碳中心 1, Pd(OAc) 2 (30% mol) PPh 3 (60% mol) Ag2CO3, THF, 2, TBAF, THF Overman, L.E. J.Am.Chem.Soc., 1999,121,5467 Me 2.2.1 Heck反应用于合成大环多烯示例 O OTBS i: Pd(OAc) 2(30 mol%) PPh 3(60 m

17、ol%) AgCO3, THF, 65 C ii: TBAF, THF 1 2 A solution of vi nyl iodide 1 (740 mg, 1.35 mmol) and THF (75 mL) was degassed (Ar, evacuate-refill), and PhsP (107 mg, 0.41 mmol), Ag2CO3 (410 mg, 1.5 mmol), and Pd(OAc)2 (46 mg, 0.20 mmol) were added. The result ing suspe nsion was stirred at room temperatur

18、e for 15 min and then heated at 65 C in a sealed tube for 12 h. A black suspension resulted after 10-20 min at 65 C . After GC analysis of a filtered aliquot showed that the reaction had not proceeded to completion, additional PhP (107 mg, 0.41 mmol), Ag2CO3 (410 mg, 1.5 mmol), and Pd(OAc)2 (46 mg,

19、0.20 mmol) were added, and the black suspensionwas stirred in a sealed tube at 65 C for an additional 6 h. The suspension was then cooled to room temperature and filtered through a plug of silica gel (1.5 cmx 12 cm, EtOAc), and the filtrate was concen trated to give the crude Heck product as a yello

20、w oil. This sample was dissolved in THF (4 mL), and TBAF (1.0 M solution in THF, 2.0 mL) was added. The result ing solutio n was maintained at room temperature for 20 h and que nched with saturated aqueous NHkCI (20 mL). The resulting mixture was extracted with CH 2CI2 (3 x 20 mL), the combined orga

21、nic layers were dried (NaSO4), filtered and concentrated, and the residue was purified by flash chromatography (4:1 hexanes-EtOAc) to provide 370 mg (90%) of tricyclic allylic alcohol 2 as a pale yellow oil: Rf=0.25(5:1 hexanes-EtOAc). 3. 分子间的Heck反应 3.1常规分子间Heck反应 端基烯烃与卤代芳香烃发生分子间 Heck反应，是研究最早的一类反应。这

22、类反应 已经成为芳烃烷基化重要反应。 该类反应在卤代物中，卤素的B位的碳原子上不能有SP3杂化的氢原子。主要是因 为这类卤代物形成烷基钯络合物时，氢化钯的消除反应速度大于烯烃的加成反应，因此 仅有消除产物。卤代芳烃、卤代杂环、卤化苄、卤代乙烯等都能较好的反应。但其他一 些卤素的B位的碳原子上没有SP3杂化的氢原子存在的化合物由于种种原因也不能正常 反应，例如：卤代甲烷、卤代乙酸乙酯、苯甲酰甲基溴等。该类反应常用碘代物和溴代 物为反应底物，碘代物相对溴代物反应活性要高。氯代物反应活性很差（几乎不反应或 者收率很低）。 在取代碘代物参与的反应中，取代基可以很广泛的使用，但邻位的苯甲酰基取代碘 化物

23、很难反应。当有强烈供电子基团时，芳基溴参与的反应收率也很低。其主要原因是 在反应中膦配体被季化与卤代物被还原。当使用P（0-t0l）3作为配体时，可以有效的避免 配体的季化。另外，当有强烈的供电子基团时，烯烃的活性也很重要。低活性烯烃参与 的反应收率也较低。 决定烯烃活性的主要因素是烯烃双键碳原子取代基的大小和数目。一般情况下，取 代基越大，数目越多，反应速度越小，收率越低。当一些烯烃反应活性较差时，通常可 以得到卤化物二聚的副产物。一般说来，共轭二烯和a 85perce nt): 3.1.2不饱和酮的Heck反应标准操作 O Pd(OAc) 2 POT, DMF, DIEA O A mixt

24、ure of 4-bromotolue ne (10.0 mmol), Cyclohex-2-e none (10 mmol), palladium acetate (0.1 -0.5 mmol), tri(o-tolyl) (0.2-1 mmol,催化剂的 2-4 倍的量)and DIEA (30 mmol) in DMF (30 mL) was heated under N2 at 100 oC for 6-12 h. The reaction mixture was cooled, diluted with 50 mL of water and extracted with ether

25、(2 x 50 mL). The combined organic porti on was washed with brine soluti on, dried over an hydrous magn esium sulfate and fin ally filtered. Evaporatation of the volatiles under reduced pressure purification with column chromatography to give the product. Note:有时可以分离到双键还原的产物 3.1.3杂环芳香卤代物和不饱和羧酸酯的Heck反

26、应标准操作一 A suspension of ArBr (68.4 mmol), Pd(dppf)Cl 2 (5 g, 6.84 mmol), tetrabutylammonium iodide (30 g, 82 mmol) and K2CO3 (28 g, 205 mmol) in N,N-dimethylformide (130 mL) was degassed via three vacuum/nitrogen ingress cycle, and then added methyl acrylate (17.6 g, 205 mmol), the mixture was stirre

27、d at 100 oC overni ght. To the mixture was added water; the aqueous layer was extracted with Et2O (3 X00 ml). The combined organic phases were washed by brine, dried over MgSO 4, filtered and concentrated. The residue was purified by colu mn chromatography to afford the product(, yield50%). 3.1.4杂环芳

28、香卤代物和不饱和羧酸酯的Heck反应标准操作二 A suspensionof ArBr (170mmol), Pd(OAc)2 (1.9g, 8.5mmol), tetrabutylammonium iodide (55.0g, 170mmol) and KOAc (5.01g, 511mmol) in N,N-dimethylformide (200 mL) was degassed via three vacuu m/n itroge n in gress cycle, and the n added methyl acrylate (46.0mL, 511mmol), the mixtu

29、re was stirred at 100 oC overni ght. To the mixture was added water; the aqueous layer was extracted with Et2O (3 300 mL). The combined organic phases were washed by brine, dried over MgSO 4, filtered and concentrated. The residue was purified by column chromatography to afford the product (15 g, yi

30、eld 50%). Note: Pd(OAc)2的质量有时是实验成败的关键， 3.1.5芳香卤代物和不饱和羧酸的 Heck反应合成反式 3-芳基不饱和酸示例 Br *COOH Pd(OAc) 2, Et 3N CH 3CN Br 3 COOH A solution of compound 1 (2.8 g, 10 mmol), compound 2 (0.9 mL, 12.5 mmol), Pd(OAc)2 (0.022g, 0.01 mmol), Et3N (3.5 mL, 25 mmol) and 4 mL aceto nitrile was heated in a steam bath

31、for 1 hour. After the react ion mixture had bee n cooled, it was diluted with 250 mL 10% aq. HCl. The solid formed was collected by filtration and re-crystallized from ethanol to give compound3 (1.86 g, yield 82%), mp 215-216.5C . 3.1.6非共轭双键Heck反应示例 ArX + OEt (3 eq.) OEt 1. 3 mol% Pd(OAc) 2 2 eq. Bu

32、 4NOAC 1.5 eq. K 2CO3 1 eq. K 2CO3, DMF, 90 C 2. 2N HCl, rt, 10 min Ar CHO Typical procedure for the preparati on of cinn amaldehyde: To a stirred solution of p-iodoanisole (0.117 g, 0.5 mmol) in 2.0 mL of DMF were added acrolein diethyl acetal (0.229 mL, 1.5 mmol), nBu4NOAc (0.302 g, 1.0 mmol0, K2C

33、O3 (0.104 g, 0.75 mmol), KCl (0.037 g, 0.5 mmol), and Pd(OAc) 2 (0.003 g, 0.015 mmol). The mixture was stirred for 1.5 h at 90oC. After cooling, 2 N HCl was slowly added and the reaction mixture was stirred ar room temperature for 10 min. Then, it was diluted with ether and washed with water. The or

34、ga nic layer was dried over NaSO4 and concen trated un der reduced pressure. The residue was purified by chromatography (silica gel, 35 gn-hexa ne/ethylacetate 90/10 v/v) to give 0.071 g (88%) of p-methoxyci nn amaldehyde. 3.2不对称分子间Heck反应 Heck芳基化反 1992年，Tamio Hayashi等报道了手性钯催化的环状烯烃的不对称 应。 Pd(OAc) 2-2

35、(R)-BINAP base, benzene, 40C 1a: Ar = Ph (96% ee) 1b: Ar = p-CIC6H 4 (96% ee) 1c: Ar = p-MeOC 6H4 (87% ee) 1d: Ar = 2-n aphthyl (96% ee) Tamio Hayashi, Pure KuehIein, K. Synlett 1995, 441 碘盐参与的Heck反应条件也比较温和，用水作溶剂反应较快，适用于一些惧怕激 烈反应条件的底物。对于二芳基碘盐的Heck反应，一般常温下得到一取代的产物，回 流条件下得到二取代产物。 、丿H + ph2l+BF4 Pd(OAc

36、) 2 (2mol%) CH3CN/H2O(5:1), rt Ph OH Kang, S.-K. J. Org. Chem.1996, 61,2604 酰氯参与的Heck反应一般在非极性溶剂中使用弱碱即可，无需膦催化剂，而且所 需钯催化剂用量极少(0.005 mol%) COCl Br Pd(OAc)2, BnNMe 2, p-xylene,100-130 C X Br NaOAc, DMF, 100-130 C Y Spencer, A.J. Orga no met. Chem.1984, 265, 323 将酸酐应用于Heck反应时20世纪末才发现的，它的优点在于不需要任何碱的存 在。 P

37、dCl2, NaBr (ArCO 2)O + _ R “ NMP,100 C Guertler, C. Chem. Eur. J 1999, 5, 3107 3.3.1重氮盐参与的 Heck反应示例 N2BF4 OMe OR 0.01 eq Pd-cat Solve nt 40-60 C OMe Table 1. Heck Reacti on of p-Methoxyphe ny Idiaz onium Tereafluoroborate With Acrylic Acid Esters En try Solve nt R Catalyst (mol%) Yield 1 Metha nol C

38、H3 Pd/Ca (1) 95 2 Etha nol C2H5 Pd/C a (1) 98 3 Etha nol C2H5 Pd/Al 2O3 a (1) 89 4 Etha nol C2H5 Pd/BaSO4 a (1) 94 5 DMSO C8H17 Pd/C a (1) 67 6 CH3CN C8H17 Pd/C a (1) 5 7 Tolue ne C8H17 Pd/C a (1) 5 8 2-EH b (1) C8H17 Pd/C a (1) 5 9 Etha nol C2H5 Pd/C c (1) 31 a The Palladium is 5% of weight on the

39、corresponding catalyst support. b 2-EH = 2-ethylhexan-1-ol. c Already used catalyst. Beller, M.; Kuehlein, K. Synlett 1995, 441 Gen eral procedure for the syn thesis of ci nn amic acid esters: 30 mmol of corresp onding diaz onium salt and 60 mmol of acrylic acid ester are suspe nded in 40 mL of the solve nt. Subseque ntly, 0.6 mmol of palladium on activated charcoal (5% weight) is added at 0C. The n the react ion mixture is heated to 60 C