甲基醚的脱甲基反应

1、经典合成反应标准操作酚醚去甲基化反应 经典化学合成反应标准操作目 录1前言22酸性试剂32.1浓HI，HBr，HCl32.248% HBr 加入相转移催化剂32.3BBr3, BI3, BCl342.4BX3和Me2S的络合物52.5BBr3/NaI/15-crown-562.6Me2BBr72.7AlX3/CH3CN, AlX3/CH2Cl2,82.8AlBr3/EtSH，AlCl3/EtSH, AlCl3/HSCH2CH2SH，AlCl3/EtSH/CH2Cl283碱性试剂93.1氨基钠93.2N-甲基苯基氨基钠/HMPT93.3EtSNa104其它试剂114.1Me3SiI114.2Li

2、Cl/DMF124.3吡啶盐酸盐141前言酚羟基广泛存在天然产物中，酚羟基易被氧化、亲电试剂取代或形成氧负离子进行亲核反应，因此天然产物的合成中常先将其保护起来，然后在合成的最后通过去保护策略游离出酚羟基。使用甲基作为酚羟基的保护基，形成甲基芳基醚，从而通过去甲基化还原出酚羟基一直是非常实用、也广泛采用的策略之一。去甲基化的方法已经发展了相当的多，并不断在开发新的方法。在1954年1，1965年2， 1967年3， 1983年4，1987年5，1988年6和1996年7，都有一篇综述对去甲基化方法进行归纳和总结，在JOHN ILEY & SONS公司出版的PROTECTIVE GROU

3、PS IN ORGANIC SYNTHESIS一书中也有专门的章节阐述去甲基化方法。在这，编者着重列举一些适用范围广，仅使用常规试剂的去甲基化方法，并从三个方面加以归纳总结：1，酸性试剂；2，碱性试剂；3，其它类型试剂。事实上，很多甲基芳基醚的去甲基化方法也适用于甲基烃基醚，反之亦然。因此，在本文的典型操作列举的范例中可以看到一些底物是甲基烃基醚。2酸性试剂2.1浓HI，HBr，HCl这是最为经典和简单的甲基芳基醚水解去甲基的方法。一般使用过量的浓HI酸回流下、或者大大过量的48% HBr8或37% HCl在HOAc或Ac2O中回流，反应完后，浓缩去除过量的酸，加入水，用有机溶剂萃取，然后进一

4、步纯化即可。特点是操作和后处理简单、方便。但要求底物对强酸稳定，对于有些底物，易形成卤代苯副产物。范例：Typical Pocedure. 8 The ether (300 mg) was dissolved in 48% HBr (50 mL) and heated for 1 hr under reflux. The reaction mixture was evaporated to dryness and extracted with ether. The ethereal extract was washed with sodium carbonate solution and wa

5、ter, dried and evaporated. The residue was recrystallized from chloroform to give the product (120 mg, 40%). 2.248% HBr 加入相转移催化剂在48%HBr中加入相转移催化剂是对仅使用强质子酸如48%HBr的改进。加入相转移催化剂后，能提高去甲基化的效率，大大缩短反应的时间。此反应是在一个多相体系（水和有机）中进行，可使用的相转移催化剂有四丁基溴化铵，十六碳烷基三丁基溴化磷,四辛基溴化铵，三辛基甲基溴化铵等。对于甲基芳基醚，一般使用5 mol量的HBr，对于甲基烃基醚，一般使用10

6、 mol量的HBr；值得注意的是，反应的收率和时间不是依赖于使用那一种相转移催化剂，而是依赖于相转移催化剂的浓度和其在有机相的溶解度。范例：Table 1. Cleavage of Ethers with 47% HBr in Presence of Hexadecyltributylphosphonium BromideR1 or ArR2 or RMol of HBrMol of CatalystTime (hrs)Yield (%)a ofR1Br or RBrArOHn-C4H9n-C4H9100.1889n-C8H17n-C8H17100.1591n-C16H33CH350.1388

7、C6H5CH350.15-91C6H5n-C4H950.12485904-t-Bu-C6H4CH350.18-904-t-Bu-C6H4n-C4H950.1248691a) Yield of isolated productTypical Pocedure.9 Cleavage of Di-n-octyl Ether. Di-n-octyl ether (12.1 g, 0.05 mol), 47% aqueous hydrobromic acid (56mL, 0.5 mol), and hexadecyltributylphosphonium bromide (2.5 g, 0.005 m

8、ol) are mixed in a flask equipped with a magnetic stirrer and reflux condenser, and heated at 115°C (inner temperature) with stirring for 5 hrs. After this time GLC analysis (SE 30, 3% over chromosorb sulfate, and distilled to give pure 1-bromooctane. The organic layer is separated, dried with

9、sodium sulfate, and distilled to give pure 1-bromooctane; yield: 17.5 g (91%), bp 88°/torr. By treating the distillation residue with hexane, 2.3 g (92%) of pure phosphonium bromide are recovered, mp 54-56°C. In the case of aryl alkyl ethers, aqueous alkaline extraction of the organic phas

10、e affords the corresponding phenol.2.3BBr3, BI3, BCl3BBr3是一种温和、优良的去甲基化试剂，并且不影响分子中的酯基和双键，在许多天然产物的全合成中常使用它。一般使用CH2Cl2, benzene, pentane作为溶剂，在-78 到室温下进行。有一点需注意，当底物分子中杂原子数多时，应增加BBr3量。使用BBr3有一个最大的缺点是BBr3对空气敏感，使用时会冒出大量气雾；并在加水后处理时常出现大量的络合物，此时最好使用其它的方法，否则后处理艰难并导致收率下降。BI3, BCl3的使用如同BBr3。范例：Table 2. Cleavage

11、of Ethers by Boron TribromideEtherAlcoholYield (%)BromideYield (%)Et2OEtOH61EtBr86i-Pr2Oi-PrOH50i-PrBr80n-Bu2On-BuOH62n-BuBr77Ph-O-Pr-iPhOH64i-PrBr62Ph-O-Bu-nPhOH75n-BuBr7681-87-PhCH2-O-Pr-nn-PrOH71PhCH2Br75General Procedure for Cleavage of Ether with BBr3. 10 A weighed quantity of the ether (usuall

12、y 15 to 20 g) is introduced into the reaction flask and cooled in an ice-bath. The calculated quantity of boron tribromide is slowly introduced through a dropping funnel. In all cases boron tribromide and ether are allowed to react in the ratio of 1 mol of boron tribromide to 3 mol of ether. After a

13、ddition of boron tribromide, the reaction mixture is heated on a water bath for 40 min. The alkyl bromide is distilled directly from the reaction mixture. After removal of the alkyl bromide by distillation, the residure remaining in the flask is hydrolyzed with a minimum amount of 10% sodium hydroxi

14、de solution. The resulting solution is acidified with hydrochloric acid and extracted with ether.2.4BX3和Me2S的络合物其为BBr3的改良方法。BBr3或BCl3和Me2S的络合物是固体物，容易制备并在惰性气体中能长期保存。一般使用2到4倍量即可。范例：Table3. Cleavage of Ethers with BBr3.S(CH2)2 ComplexEtherRatio of Reagent/EtherTimea (hrs)ProductYield (%)Ph-O-Me4.012PhO

15、H86b3.971267c3.971250c3.791278c3.872464ca) Reaction run at 83°C. b) GLC yield. C) Isoated yield.General Procedure for the Cleavage of Ethers with Boron Trihalide-Methyl sulfide Complex. 11To a flame-dried 100 mL flask under an atmosphere of nitrogen is added 1,2-dichloroethane (30 mL) and an am

16、ount of boron trihalide-methyl sulfide complex as indicated in Table 3. To this solution is added the desired number of equivalents of the aryl ether. The reaction mixture is stirred at reflux and monitored by either TLC or GLC where convenient. When the starting material disappears, the reaction mi

17、xture is hydrolyzed by adding water (30 mL), stirring for 20 min and diluting with ether. The organic phase is separated and washed with 1 M NaHCO3 and the phenol is subsequently taken up with 1 N NaOH (3×20 mL). The combined NaOH washings are acidified and the product is subsequently extracted

18、 into ether, dried (MgSO4) and the solvent is removed in vacuum.2.5BBr3/NaI/15-crown-5这种体系为比BBr3更强的去甲基化方法。也可用于脱除烷基甲基醚。范例：Table4. Dealkylation of Alkyl Methyl Ethers with BBr3-NaI-15-crown-5Methyl EtherAlcoholYield (%)100100759310a) Yield of isoated alcohol.Typical Procedure. Cleavage of 3-Phenylprop

19、anol Methyl Ether. 11To a stirred solution of 3-phenylpropanol methyl ether (103 mg, 0.687 mmol) in dry methylene chloride (0.5 mL) is added 0.3 M solution of 15-crown-5 (13.7 mL, 6 equiv.) with NaI in methylene chloride followed by addition of 1 M solution of BBr3 (2.1 mL, 3 equiv.) in methylene ch

20、loride at -30°C under argon. The reaction mixture is stirred at the same temperature for 3 hrs, quenched by the addition of saturated aqueous NaHCO3 solution (2 mL) and worked up in the usual manner. Chromatographic purification of the crude product gives the pure alcohol (93 mg, 100%), identic

21、al in all respects with an authentic sample.2.6Me2BBr文献报道，这个试剂去甲基化经由SN2机理，因此，非常有效的只是断裂C-O键，从而形成酚或醇，不易产生溴代副产物。范例：Table5. Cleavage of Ethers with (CH3)2BBrSubstrateReagent (equiv.)Temp. (°C)Time (hrs)ProductYield (%)30-2518931.30-253751.60-256494.07030724.0703696a) Yield of isoated Product.Typica

22、l Procedure. Cleavage of 1-Methoxydecane. 12 To a cold (0°C), stirred solution of 1-methoxydodecane (1.03 mmol) and triethylamine (0.21 mmol, to neutralize traces of free acid) in dry methylene chloride (4.1 mL) under argon, is added a solution of dimethylboron bromide (1.34 M, 0.99 mL) in meth

23、ylene chloride. The cooling bath is then removed and the resultant solution is then stirred at room temperature for 3 hrs. The reaction mixture is then cooled to 0°C, quenched with saturated aqueous sodium bicarbonate (2 mL) and diluted with ether (30 mL). The organic layer is separated, washed

24、 with saturated sodium bicarbonate (2 mL), water (2 mL) and brine (2 mL). The aqueous washings are extracted with ether and the organic layers are combined. After drying the resultant solution is concentrated and subjected to flash chromatography to provide pure 1-dodecanol (89%).2.7AlX3/CH3CN, AlX3

25、/CH2Cl2,AlCl3/CH3CN13和AlBr3/CH3CN14是另外一类常用的去甲基化方法，其操作类似BBr3的使用，只是一般反应温度在0-室温。范例：Typical Procedure. 13 To dichloromethane (1 mL) or CH3CN (1 mL) was added aluminum chloride (3.0 mmol) at 0 OC. The resulting solution was warmed to room temperature, and the ether (1.0 mmol) was added with stirring. Aft

26、er being stirred for 3-12 h, the reaction mixture was poured into water, acidified with dilute HC1, and extracted with dichloromethane. The organic layer was treated as usual to give a crude product. Chromatography over a silica gel column gave the desired product.2.8AlBr3/EtSH，AlCl3/EtSH, AlCl3/HSC

27、H2CH2SH，AlCl3/EtSH/CH2Cl2AlBr3/EtSH, AlCl3/EtSH, AlCl3/HSCH2CH2SH体系的活性很高，分子中酯、醛、酮、双键不稳定，但酯在AlCl3/EtSH/CH2Cl2体系相对稳定。范例：General Procedure for Demethylation. 15 To a stirred solution of aluminum halide in ethanethiol cooled in an ice-water bath was added the substrate. The reaction was monitored by TLC

28、 (aluminum halide was quenched by methanol in the capillary). The reaction mixture was poured into water, acidified with dilute HC1, and extracted with dichloromethane. The organic layer was shaken with brine, dried (Na2SO4), filtered, and then evaporated to leave a crude material, which was purifie

29、d by chromatography over a silica gel column. AlCl3/EtSH/CH2Cl2体系：15 To a mixture of dry ethanethiol (1 mL) and dichloromethane (1 mL) was added aluminum chloride (0.40 g, 3.0 mmol) at 0 OC. The resulting solution was warmed to room temperature, and the ether (0.194 g, 1.0 mmol) was added with stirr

30、ing. After being stirred for 9.5 h, the reaction mixture was poured into water, acidified with dilute HC1, and extracted with dichloromethane. The organic layer was treated as usual to give a crude product. Chromatography over a silica gel column gave the desired product (0.157 g, 95.5%) identical w

31、ith an authentic sample. AlCl3/EtSH 体系：15 To a solution of aluminum chloride (47 mg, 0.35 mmol) in dry ethanethiol (1 mL) was added the ether (11 mg, 0.03 mmol) at 0 "C. After being stirred for 2.5 h at 0 "C, the reaction mixture was poured into water and extracted with dichloromethane. Th

32、e usual workup of the organic layer gave the product: 7.5 mg (81.5%). 3碱性试剂3.1氨基钠适合于苯环上没有电负性取代基，否则易发生birch还原反应16。3.2N-甲基苯基氨基钠/HMPT对于苯环上有电负性取代基的底物易发生取代反应。范例：Table7. Dealkylation of Alkyl Aryl Ether with sodium N-Methylanilide in presence of HMPTSubstrateTime (hrs)Temp. (°C)ProductYield (%)a6.512

33、09510120800.59595241209099585685901712070a) Yield of isoated Product.Typical Procedure. Cleavage of 1,2,4-Trimethoxybenzene. 17 N-Methylaniline (2.68 g, 25 mmol) is added dropwise at 65°C to a stirred suspension of sodium hydride (0.6 g, 25 mmol) in sodium-dried xylene (5 mL) and HMPT (4.26 g,

34、25 mmol, distilled over calcium hydride and stored in dark over molecular sieves, 8A°). After 15 min, the ether (12.5 mmol in the minimum amount of xylene) is added and the mixture is heated at 85°C. The reaction is monitored by GLC (3 m SE 30 column) and by TLC. When the starting material

35、 disappears (6 hrs) the mixture is poured into water, acidified with dilute hydrochloric acid, and the product is extracted with ether. The ether phase is washed with dilute hydrochloric acid (2×90 mL) to remove HMPT and the amines and then the product is extracted with 10% sodium hydroxide sol

36、ution (2×90 mL). The aqueous phase is acidified with dilute hydrochloric acid and extracted with ether (3×90 mL). The organic phase is dried over calcium chloride and concentrated on a rotary evaporator to give pure 2,5-dimethoxyphenol; yield: 1.9 g (90%). The product may be further purifi

37、ed by column chromatography on silica gel.3.3EtSNa在EtSNa/DMF体系中，双键和溴代物不受影响；有时具有选择性去甲基化，如下表。范例：Table 8. Dealkylation of Ethers by Sodium EthanethiolateEtherEquiv. of ReagentTime (hrs)ProductYield (%)2.53962.53965384539853892.52093-Typical Procedure. Dealkylation of m-Methoxytoluene. 18 Ethanethiol (1

38、.25 g, 11.8 mmol) dissolved in dry DMF (20 mL) is added to a suspension of sodium hydride (1.0 g of a 50% oil dispersion) in dry DMF (10 mL) under an atmosphere of nitrogen. The mixture is stirred for 5 min before solution of m-methoxytoluene (1.09 g) in dry DMF is added. The solution is then reflux

39、ed for 3 hrs. The cooled mixture is acidified with 10% aqueous hydrochloric acid and extracted with ether. The ether layer is washed with water and extracted with 5% sodium hydroxide. The alkaline extracts are then acidified and reextracted with ether. The ethereal solution is washed with water, dri

40、ed and evaporated to give m-cresol as a light brown oil; yield: 0.85 g (78%).4其它试剂4.1Me3SiI另一种常用的去甲基试剂，在此体系中，双键、三键、酮羰基、氨基和卤代物稳定，但苄醚、三苯甲基醚、叔丁基醚不稳定。三甲基碘硅烷能裂解酯但比醚慢。范例： Table 10. Dealkylation of Ethers by Trimethylsilyl IodideR1R2Reaction Conditionsa Time / TemperatureYield of products (%)R1-OSi(CH3)3R2

41、Ic-C6H11CH36 hrs / 25°955c-C6H11C2H512 hrs / 25°4951c-C6H11t-C4H90.1 hrs / 25°b1000c-C6H11C6H5CH20.1 hrs / 25°1000CH32.5 hrs / 25°1000C6H5CH348 hrs / 25°100-3-CH3C6H4C2H5140 hrs / 25°b100-a) Solvent CDCl3, unless otherwise mentioned. b) In CCl4.General Procedure fo

42、r Dealkylation of Ether. 19 To a 2 M solution of ether (1 equiv.) in a suitable solvent (Table 10) is added neat trimethylsilyl iodide (1.3 equiv.) through a dry syringe. The reaction is maintained at temperature indicated in Table 10 and monitored by NMR for completion. Yields are calculated by NMR

43、 integration of pertinent peaks. For isolation of the alcohols, at the completion of the reaction, the excess trimethylsilyl iodide is destroyed and the intermediate trimethylsilyl ether formed during the reaction is hydrolyzed to alcohol by pouring the reaction mixture into methanol (4 equiv.). The

44、 volatile components are removed at reduced pressure and the residue is taken up in ether, washed with aqueous sodium bisulfite, aqueous sodium bicarbonate and brine and dried. The residue left after evaporation of solvent is further purified (if necessary) by column chromatography on silica gel.4.2

45、LiCl/DMF当邻位和对位有吸电子基团存在时，此体系去甲基化容易进行。底物中有醛和酯时，去甲基需更长的时间，甲酯会去甲基形成酸。范例： Table 12. Cleavage of Alkyl Aryl Ethers with LiCl in DMFRX1X2Reaction Time (hrs)Yield (%)aMe2-NO2H698Me3-NO2H650Me4-NO2H2498Et2-NO2H2290i-Pr2-NO2H2435PhCH22-NO2H2298Et4-NO2H2410Me2-NO24-Br495Me2-ClH7255Me2-BrH7267Me2-CHOH2270Et2-CH

46、OH2225i-Pr2-CHOH225Me2-CO2MeH2290CH2CO2Me2-MeH225Typical Procedure. Cleavage of 2,3-Dimethoxybenzaldehyde. 20 2,3-Dimethoxybenzaldehyde (1.0 g, 6 mmol) and LiCl (0.76 g, 18 mmol) are heated in boiling DMF (10 mL), the reaction being monitored by GLC. When the starting material disappears, 10% aqueou

47、s NaOH (30 mL) is added; the solution is washed with ether (2×25 mL), then acidified with 10% aqueous HCl (50 mL), and extracted with ether (2×25 mL). The organic phase is washed with brine (30 mL), dried (sodium sulfate) and concentrated in a rotary evaporator to afford 2-hydroxy-3-methox

48、ybenzaldehyde (0.88 g, 98%).4.3吡啶盐酸盐将底物和大大过量的吡啶盐酸盐混合均匀，加热到200左右进行，反应完后，常规后处理即可21。范例：Demethylation of p-Dihydrothebainol Methyl Ether with Pyridine Hydrochloride. 21 A mixture of 204 mg. of -dihydrothebainol methyl ether and 247 mg. of freshly fused pyridine hydrochloride was heated for four hours at

49、 195- 00' (bath). The cooled brownish residue was dissolved in water, niade basic with potassium hydroxide containing hydrosulfite, and extracted several times with chloroform. The chloroform, after processing, was found to contain only a trace of non-volatile residue. The aqueous alkaline layer

50、 was then carbonated to excess and extracted several times with butanol. The butanol extracts were washed, filtered through anhydrous sodium sulfate, and concentrated under nitrogen. Crystallization occurred during the concentration, and the residue melted at 239-242' dec. (162 ing.). Several crystallizations from butanol gave 72 mg. of small prisms, m.p. 258-