甲基醚的脫甲基反應(yīng)-060120

1、經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作酚醚去甲基化反應(yīng) 藥明康德新藥開(kāi)發(fā)有限公司經(jīng)典化學(xué)合成反應(yīng)標(biāo)準(zhǔn)操作甲基芳基醚去甲基化反應(yīng)編者： 彭作中藥明康德新藥開(kāi)發(fā)有限公司化學(xué)合成部目 錄1前言22酸性試劑32.1濃HI，HBr，HCl32.248% HBr 加入相轉(zhuǎn)移催化劑32.3BBr3, BI3, BCl342.4BX3和Me2S的絡(luò)合物52.5BBr3/NaI/15-crown-562.6Me2BBr72.7AlX3/CH3CN, AlX3/CH2Cl2,82.8AlBr3/EtSH，AlCl3/EtSH, AlCl3/HSCH2CH2SH，AlCl3/EtSH/CH2Cl283堿性試劑93.1氨基鈉93.2N

2、-甲基苯基氨基鈉/HMPT93.3EtSNa104其它試劑114.1Me3SiI114.2LiCl/DMF124.3吡啶鹽酸鹽141前言酚羥基廣泛存在天然產(chǎn)物中，酚羥基易被氧化、親電試劑取代或形成氧負(fù)離子進(jìn)行親核反應(yīng)，因此天然產(chǎn)物的合成中常先將其保護(hù)起來(lái)，然后在合成的最后通過(guò)去保護(hù)策略游離出酚羥基。使用甲基作為酚羥基的保護(hù)基，形成甲基芳基醚，從而通過(guò)去甲基化還原出酚羥基一直是非常實(shí)用、也廣泛采用的策略之一。去甲基化的方法已經(jīng)發(fā)展了相當(dāng)?shù)亩?，并不斷在開(kāi)發(fā)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，都有一篇綜述對(duì)去甲基化方法進(jìn)行

3、歸納和總結(jié)，在JOHN ILEY & SONS公司出版的PROTECTIVE GROUPS IN ORGANIC SYNTHESIS一書(shū)中也有專門的章節(jié)闡述去甲基化方法。在這，編者著重列舉一些適用范圍廣，僅使用常規(guī)試劑的去甲基化方法，并從三個(gè)方面加以歸納總結(jié)：1，酸性試劑；2，堿性試劑；3，其它類型試劑。事實(shí)上，很多甲基芳基醚的去甲基化方法也適用于甲基烴基醚，反之亦然。因此，在本文的典型操作列舉的范例中可以看到一些底物是甲基烴基醚。2酸性試劑2.1濃HI，HBr，HCl這是最為經(jīng)典和簡(jiǎn)單的甲基芳基醚水解去甲基的方法。一般使用過(guò)量的濃HI酸回流下、或者大大過(guò)量的48% HBr8或37%

4、HCl在HOAc或Ac2O中回流，反應(yīng)完后，濃縮去除過(guò)量的酸，加入水，用有機(jī)溶劑萃取，然后進(jìn)一步純化即可。特點(diǎn)是操作和后處理簡(jiǎn)單、方便。但要求底物對(duì)強(qiáng)酸穩(wěn)定，對(duì)于有些底物，易形成鹵代苯副產(chǎn)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 w

5、as washed with sodium carbonate solution and water, dried and evaporated. The residue was recrystallized from chloroform to give the product (120 mg, 40%). 2.248% HBr 加入相轉(zhuǎn)移催化劑在48%HBr中加入相轉(zhuǎn)移催化劑是對(duì)僅使用強(qiáng)質(zhì)子酸如48%HBr的改進(jìn)。加入相轉(zhuǎn)移催化劑后，能提高去甲基化的效率，大大縮短反應(yīng)的時(shí)間。此反應(yīng)是在一個(gè)多相體系（水和有機(jī)）中進(jìn)行，可使用的相轉(zhuǎn)移催化劑有四丁基溴化銨，十六碳烷基三丁基溴化磷,四辛基溴化銨，

6、三辛基甲基溴化銨等。對(duì)于甲基芳基醚，一般使用5 mol量的HBr，對(duì)于甲基烴基醚，一般使用10 mol量的HBr；值得注意的是，反應(yīng)的收率和時(shí)間不是依賴于使用那一種相轉(zhuǎn)移催化劑，而是依賴于相轉(zhuǎn)移催化劑的濃度和其在有機(jī)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-C4H91

7、00.1889n-C8H17n-C8H17100.1591n-C16H33CH350.1388C6H5CH350.15-91C6H5n-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 hexad

8、ecyltributylphosphonium bromide (2.5 g, 0.005 mol) 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-bromoocta

9、ne. The organic layer is separated, dried with 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,

10、aqueous alkaline extraction of the organic phase affords the corresponding phenol.2.3BBr3, BI3, BCl3BBr3是一種溫和、優(yōu)良的去甲基化試劑，并且不影響分子中的酯基和雙鍵，在許多天然產(chǎn)物的全合成中常使用它。一般使用CH2Cl2, benzene, pentane作為溶劑，在-78 到室溫下進(jìn)行。有一點(diǎn)需注意，當(dāng)?shù)孜锓肿又须s原子數(shù)多時(shí)，應(yīng)增加BBr3量。使用BBr3有一個(gè)最大的缺點(diǎn)是BBr3對(duì)空氣敏感，使用時(shí)會(huì)冒出大量氣霧；并在加水后處理時(shí)常出現(xiàn)大量的絡(luò)合物，此時(shí)最好使用其它的方法，否則后處理艱難并

11、導(dǎo)致收率下降。BI3, BCl3的使用如同BBr3。范例：Table 2. Cleavage 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 B

12、Br3. 10 A weighed quantity of the ether (usually 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

13、 of boron tribromide to 3 mol of ether. After addition 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 hydroly

14、zed with a minimum amount of 10% sodium hydroxide solution. The resulting solution is acidified with hydrochloric acid and extracted with ether.2.4BX3和Me2S的絡(luò)合物其為BBr3的改良方法。BBr3或BCl3和Me2S的絡(luò)合物是固體物，容易制備并在惰性氣體中能長(zhǎng)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/

15、EtherTimea (hrs)ProductYield (%)Ph-O-Me4.012PhOH86b3.971267c3.971250c3.791278c3.872464ca) 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 nitroge

16、n is added 1,2-dichloroethane (30 mL) and an amount 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 th

17、e starting material disappears, the reaction mixture 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 acid

18、ified and the product is subsequently extracted into ether, dried (MgSO4) and the solvent is removed in vacuum.2.5BBr3/NaI/15-crown-5這種體系為比BBr3更強(qiáng)的去甲基化方法。也可用于脫除烷基甲基醚。范例：Table4. Dealkylation of Alkyl Methyl Ethers with BBr3-NaI-15-crown-5Methyl EtherAlcoholYield (%)100100759310a) Yield of isoated alco

19、hol.Typical Procedure. Cleavage of 3-Phenylpropanol 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 solu

20、tion of BBr3 (2.1 mL, 3 equiv.) in methylene chloride 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 produc

21、t gives the pure alcohol (93 mg, 100%), identical in all respects with an authentic sample.2.6Me2BBr文獻(xiàn)報(bào)道，這個(gè)試劑去甲基化經(jīng)由SN2機(jī)理，因此，非常有效的只是斷裂C-O鍵，從而形成酚或醇，不易產(chǎn)生溴代副產(chǎn)物。范例：Table5. Cleavage of Ethers with (CH3)2BBrSubstrateReagent (equiv.)Temp. (°C)Time (hrs)ProductYield (%)30-2518931.30-253751.60-256494.070

22、30724.0703696a) Yield of isoated Product.Typical 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

23、dimethylboron bromide (1.34 M, 0.99 mL) in methylene 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

24、(30 mL). The organic layer is separated, washed 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 pro

25、vide pure 1-dodecanol (89%).2.7AlX3/CH3CN, AlX3/CH2Cl2,AlCl3/CH3CN13和AlBr3/CH3CN14是另外一類常用的去甲基化方法，其操作類似BBr3的使用，只是一般反應(yīng)溫度在0-室溫。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 th

26、e ether (1.0 mmol) was added with stirring. After 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 desi

27、red product.2.8AlBr3/EtSH，AlCl3/EtSH, AlCl3/HSCH2CH2SH，AlCl3/EtSH/CH2Cl2AlBr3/EtSH, AlCl3/EtSH, AlCl3/HSCH2CH2SH體系的活性很高，分子中酯、醛、酮、雙鍵不穩(wěn)定，但酯在AlCl3/EtSH/CH2Cl2體系相對(duì)穩(wěn)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 t

28、he substrate. The reaction was monitored by TLC (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 evaporat

29、ed to leave a crude material, which was purified by chromatography over a silica gel column. AlCl3/EtSH/CH2Cl2體系：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

30、 ether (0.194 g, 1.0 mmol) was added with stirring. 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 t

31、he desired product (0.157 g, 95.5%) identical with an authentic sample. AlCl3/EtSH 體系：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 in

32、to water and extracted with dichloromethane. The usual workup of the organic layer gave the product: 7.5 mg (81.5%). 3堿性試劑3.1氨基鈉適合于苯環(huán)上沒(méi)有電負(fù)性取代基，否則易發(fā)生birch還原反應(yīng)16。3.2N-甲基苯基氨基鈉/HMPT對(duì)于苯環(huán)上有電負(fù)性取代基的底物易發(fā)生取代反應(yīng)。范例：Table7. Dealkylation of Alkyl Aryl Ether with sodium N-Methylanilide in presence of HMPTSubstrate

33、Time (hrs)Temp. (°C)ProductYield (%)a6.51209510120800.59595241209099585685901712070a) 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) i

34、n sodium-dried xylene (5 mL) and HMPT (4.26 g, 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

35、 column) and by TLC. When the starting material 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 pro

36、duct is extracted with 10% sodium hydroxide solution (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:

37、 1.9 g (90%). The product may be further purified by column chromatography on silica gel.3.3EtSNa在EtSNa/DMF體系中，雙鍵和溴代物不受影響；有時(shí)具有選擇性去甲基化，如下表。范例：Table 8. Dealkylation of Ethers by Sodium EthanethiolateEtherEquiv. of ReagentTime (hrs)ProductYield (%)2.53962.53965384539853892.52093-Typical Procedure. Deal

38、kylation of m-Methoxytoluene. 18 Ethanethiol (1.25 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) i

39、n dry DMF is added. The solution is then refluxed 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.

40、The ethereal solution is washed with water, dried and evaporated to give m-cresol as a light brown oil; yield: 0.85 g (78%).4其它試劑4.1Me3SiI另一種常用的去甲基試劑，在此體系中，雙鍵、三鍵、酮羰基、氨基和鹵代物穩(wěn)定，但芐醚、三苯甲基醚、叔丁基醚不穩(wěn)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 /

41、 TemperatureYield of products (%)R1-OSi(CH3)3R2Ic-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 other

42、wise mentioned. b) In CCl4.General Procedure for 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 N

43、MR for completion. Yields are calculated by NMR 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

44、 reaction mixture into methanol (4 equiv.). The 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 necess

45、ary) by column chromatography on silica gel.4.2LiCl/DMF當(dāng)鄰位和對(duì)位有吸電子基團(tuán)存在時(shí)，此體系去甲基化容易進(jìn)行。底物中有醛和酯時(shí)，去甲基需更長(zhǎng)的時(shí)間，甲酯會(huì)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-NO2

46、4-Br495Me2-ClH7255Me2-BrH7267Me2-CHOH2270Et2-CHOH2225i-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. Wh

47、en the starting material disappears, 10% aqueous 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

48、 rotary evaporator to afford 2-hydroxy-3-methoxybenzaldehyde (0.88 g, 98%).4.3吡啶鹽酸鹽將底物和大大過(guò)量的吡啶鹽酸鹽混合均勻，加熱到200左右進(jìn)行，反應(yīng)完后，常規(guī)后處理即可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 pyri

49、dine hydrochloride was heated for four hours at 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 n

50、on-volatile residue. The aqueous alkaline layer 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. 258-262&qu