PCP via Enamine Intermediate
by Xicori
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After a few trials on PCP-Synthesis via the N-Benzoylpiperidine route (they have all failed, if someone wants details, let me know), Swim has performed a PCP synthesis via the enamine route. The whole synthesis was illustrated with pictures, so that other bees get a easy to follow writeup…
Here we go:
Step 1: N-piperidin-cyclohexene
Into a 250ml RBF with a Dean Stark water-trap, a Dimroth reflux condensor and some boiling stones there were added 39,6ml of Piperidine, 34,5ml of cyclohexanone, 500mg of p-Toluene-sulfonic-acid and 100ml Toluene as solvent.
The mixture was heated with a heating mantle until all water had seperated (~5,4ml). Heating was stopped, and after the contents had cooled down the reaction mixture was washed with ~30ml of water to remove the catalyst acid. The organic phase was seperated, dried over Na2SO4 and distilled under aspirator vacuum to yield 45g of colourless, nearly smellless enamine. (b.p. ~ 108°C@good aspirator vacuum)
Apparatus for azeotropic removal of water
2) Reaction Mixture
3) water in the dean stark receiver
4) Apparatus for vacuum distillation of the reaction contents
5) distilled, nearly pure enamine in the recveiver
Note:
Piperidine is corrossive, toxic, and has a very unpleasent amine smell – avoid spilling it -> use a syringe!
Step 2: Removal of water from p-Toluene sulfonic acid Monohydrate
0,1mole (19g) of p-Toluene sulfonic acid Monohydrate were added to 40ml of Toluene, and heated under a Dean stark trap, until no more water seperated, and the distillate was completely clear. Theoretically water amount: 1,8ml
6) Apparatus
7) boiling mixture
Notes: At first 2 Layers are formed – I think the top layer consists of Toluene, and the bottom layer consists of melted P-Toluene-Sulfonic Acid Monohydrate. -> Use a magnetic stirrer to mix the two phases well. During the seperation of water the bottom layer dissappears -> anhydrous Acid dissolves into the toluene.
Step 3: Preparing of a Phenyl Magnesium Bromide-Solution in Et2O (Grignard-Rnx)
All glassware for this step should be dried in an oven. Anhydrous solvents are absolutely necessary! (use molecular sieves or Na to dry Et2O)
Into a 250ml 3-necked RBF were added 2,4g (01,1 mole) of Mg turnings, 1 small iodine xtal, and 30ml of ether. Now there were slowly added 0,1mole of bromobenzene in 15ml of Et2O. The start of the reaction is noticed by disappearing of the purple iodine-colour, and the ether beginning to boil.
Add the residual Bromobenzene at a rate that keeps the ether refluxing. When all the bromobenzene has been added reflux the mixture for additional 3 hours to finish the reaction.
reaction just started – let bromobenzene drip into the mix slowly
8) apparatus for grignard rnx – note the drying tubes on condensor and dropping funnel – an effective reflux condensor is also necessary. A liebig-condensor will not work!!
9) Closeup
Notes:
The mixture turns a bit brown during grignard reagent formation. That’s no reason to worry.
When the reaction goes to fast use a cold water bath to slow things down.
Always use magnetic stirring!
Use CaCl2-Drying tubes and an efficient reflux condensor!
Read Organikum, Vogel, etc. about grignard reactions!
Step 4: Salting your enamine from step 1 with your anhydrous acid from step 2
In a 500ml 2-Necked RBF add 16,5g of Cyclohexenyl-Piperidine (from step 1), and add 50ml of anhydrous ether. Add a stirbar, a condensor, a dropping funnel, and attach drying tubes!
Immerse the flask into an ice bath to keep temp below 5°C. Now add your anhydrous P-ToSufoAcid in Toluene, prepared in step 2. – the addition has to be done dropwise.
The enamine forms a salt with the acid (the salt isnt soluble in ether/toluene, so a white slurry is formed).
10) addition of the anhydrous p-Toluene Sulfonic Acid
11) a thick white slurry is formed
Note: use a big stirrbar to allow stirring even if the flask contents get a bit sticky
Step 4: PCP
Now cool your Phenylmagnesium-bromide solution in an ice bath, and transfer the etheral solution into a dropping funnel. All apparatus must be absolutely dry! – Do this as quick as possible to avoid reacting of the Grignard-reagent with humidity/CO2 in the air.
Now add your Grignard-Solution to the slurry produced in Step 4. Cool with ice, and add the solution dropwise! The temp should not go above 5°C. Now the slurry gets easy stirrable again. After everything is added remove the ice bath and stir for additional 30-45min.
12) Phenyl Magnesium Bromide Solution transferred into dropping funnel.
PCP通过烯胺中间体通过xicori[回到化学档案]经过几次试验对PCP的合成通过n-benzoylpiperidine路线(他们都失败了,如果有人要的细节,让我知道),游泳进行PCP通过烯胺的合成路线。配有图片的全合成,让其他蜜蜂容易遵循的文章…让我们开始吧。步骤1:n-piperidin-cyclohexene在一个Dean Stark水陷阱250ml RBF,回流冷凝器和沸腾一迪姆罗斯石头有哌啶加39,6ml,34,5ml环己酮,对p-toluene-sulfonic-acid毫升甲苯作为溶剂的500mg。将混合物加热,具有加热地幔直到所有的水分离(~ 5,4ml)。加热停止,和之后的内容已经冷却反应混合物用~ 30ml水去除催化剂的酸。有机相分离,Na2SO4干燥和蒸馏下抽气真空产生45g的无色、几乎无味的烯胺。(108°B.P. ~ @好抽真空)对于水共沸除去装置2)反应混合物3)水在院长-鲜明的接收器4)用于减压蒸馏的反应物的装置5)蒸馏,几乎纯的烯胺在recveiver注:哌啶是腐蚀性的,有毒的,有一个非常不愉快的胺味–避免溅->使用注射器!步骤2:从对甲苯磺酸一水合物去除水0,1mole(19克)对甲苯磺酸水合物加入40ml甲苯,加热一个分水器下,直到没有更多的水和油分离,是完全清楚。从理论上1,8ml水量:6)设备7)沸腾混合物注:在前2层形成–我觉得顶层由甲苯和底层由熔化的对甲苯磺酸一水合物。->使用磁力搅拌器混合两相好。在分离水的底层消失->无水氢氟酸溶解在甲苯。步骤3:一个苯基溴化镁在乙醚溶液制备(Grignard Rnx)这一步的所有玻璃器皿都要在烤箱里烘干。无水溶剂是绝对必要的!(用分子筛或钠干乙醚)到250ml 3-necked RBF增加2,4g(01,1摩尔)镁屑,1小碘晶体,和30ml的醚。现在有0,1mole慢慢加在15ml乙醚溴苯。开始的反应是由碘紫色消失的注意,和醚开始沸腾。速度使乙醚回流加入剩余的Bromobenzene。当所有的溴苯已添加回流混合额外的3个小时完成的反应。反应刚开始–让溴苯滴入慢慢混合8)格氏RNX–注意干燥管冷凝器和滴液漏斗–有效回流冷凝器也是必要的设备。一个李比希冷凝器不工作!!9)特写笔记:混合物变成一位布朗格氏试剂形成过程。这是没有理由担心。当反应进入快速使用一个冷水浴,以减缓事情。总是用磁力搅拌!用氯化钙干燥管和一个高效的回流冷凝器!读Organikum、沃格尔等关于格氏反应!步骤4:腌制你的烯胺与你无水酸从2步,1步在500ml 2-necked RBF加环己烯基哌啶16,5g(步骤1),加入无水乙醚50ml。添加一个搅拌棒,一个冷凝器,滴液漏斗,把干燥管!将瓶在冰浴保存温度低于5°现在增加你在Toluene p-tosufoacid步骤2制备无水。–除了要做滴。烯胺与酸形成盐(盐不醚/甲苯,溶所以白浆形成)。10)的无水甲苯磺酸加11)形成了一个厚的白色浆料注意:使用一个大的stirrbar允许搅拌即使瓶中的内容有点粘步骤4:PCP现在酷你的苄基溴化镁溶液在冰浴中,并转移到一个虚形液滴液漏斗。所有设备必须完全干燥!–做到尽可能快地避免在空气/二氧化碳湿度的格氏试剂反应。现在添加格氏溶液在步骤4中产生的泥浆。冷冰,并添加液滴!温度不应超过5°现在浆变得很容易stirrable再次。在一切都增加了额外的时间去除冰浴搅拌。12)转移到滴漏斗的苯基镁溴溶液。
正在翻譯中..