Main Index Search Register Login Who's Online FAQ Links | ||||
1 Online, 0 Active | You are not logged in |
|
Novel Discourse | |||
All 31 posts | Subject: New route to PEAs? | Please login to post | Down | |||||
Sonson (Stranger / Eraser) 09-03-01 12:52 No 209740 |
New route to PEAs? | |||||||
I don't know if this reaction/pathway to PEAs has been discussed here before, but I think this can be a promising route to 2C-B or 2C-T's. First one reacts 1,4-dimethoxybenzene (or 2-Br-1,4-diMeObnz) with HCl and formaldehyde in dioxane to get the chloromethylderivate. (see collect. Czech. Chem. Commun. 55, pp788, 1990 for this reaction on various 2-alkylthio-1,4-diMeO-benzenes - fairly good yields, 60-70%, mostly due to wasteful recryst.) The chloromethylderivate is then reacted with NaCN in DMF to yield the acetonitrile (80-90%). (same reference as above) The acetonitrile can then be reduced to the amine with various reagents: Na/EtOH, tert-butylammoniumborohydride in DCM, Ra-Ni, hydrogenation, LAH, MeSiCl/NaBH4 to name a few. What do you think? BTW the acetonitrile can be made from the benzaldehyde with ethylchloroformate and MgSO4 according to a Arch. Pharm. ref (they made mescaline this way). |
||||||||
Antoncho (Official Hive Translator) 09-03-01 16:24 No 209758 |
Re: New route to PEAs? | |||||||
i don't think dimethoxybenzene can bee used in this rxn... This has already been discussed some time ago and i believe Rhodium said that the ring is so activated in it that it's never possible to stop the rxn at that stage and dichloromethyl-comp'ds are always gotten from it. Now, if you subst 1st the ring w/bromine that should prevent that from happening... And thiols, too... However, am i not right that -SH group is an electron donor and should yet further activate the ring?? Then what does the Czech patent say? Do you have any more details on this? Antoncho |
||||||||
Rhodium (Chief Bee) 09-03-01 20:35 No 209810 |
Re: New route to PEAs? | |||||||
Is the Czech paper in english/german, so that it can be understood? Otherwise, it seems like Cesium at this board could translate it. |
||||||||
halfapint (Ubiquitous Precursor Medal Winner) 09-04-01 01:06 No 209857 |
Re: New route to PEAs? | |||||||
Sonson, where's the nitrogen source in this for the nitrile? turning science fact into <<science fiction>> |
||||||||
Sonson (Stranger / Eraser) 09-04-01 14:02 No 210011 |
Re: New route to PEAs? | |||||||
Rhod: Its in english. I will transcribe parts of the experimental so we can discuss it in detail. Halfapint: Well...i forgot to mention that they used KCN too...sorry. |
||||||||
Sonson (Stranger / Eraser) 09-05-01 09:03 No 210276 |
Re: New route to PEAs? (Rated as: good read) |
|||||||
OK, here is the detailed procedure: A mixture of 10ml 39% aqueous formaldehyde, 5ml hydrochloric acid and 20ml dioxane was saturated for 10min with HCl (temp rose to 65C). The stirred mixture was treated over 5min with a solution of 12.2g 2-(pentythio)-1,4-dimethoxybenzene in 10ml dioxane, it was stirred for 30 min at 60-65C, poured to 100ml water and extracted with ether. The extract was washed with water and processed. The residue (12.2g) was crystallized from a mixture of acetone and light petroleum giving 0.6g 2,2',5,5'-tetramethoxy-4,4'-bis(pentylthio)diphenylmethane, mp 104-105C (acetone) Evaporation of the mother liquor and crystallization of the residue from light petroleum gave 9.4g (64%) of 2-(chlorometyl)-1,4-dimethoxy-5-(pentylthio)benzene (I), mp 64-66C (2,5-dimethoxy-4-(pentylthio)phenyl)acetonitrile The suspension of 82.2g I in 315ml DMF was treated with 41.g NaCN, the mixture was stirred for 30min at 40C and for 5h at 95C. After cooling it was diluted with 500ml water and extracted with benzene. Processing of the extract gave 90g of a crude product which was crystallized first from 130ml ethanol and the from 210ml cyclohexane giving 68.2g of the product. Mp 85-88C Pretty neat, huh? |
||||||||
Rhodium (Chief Bee) 09-05-01 09:21 No 210277 |
Re: New route to PEAs? | |||||||
VERY good! This might be a new major road to PEA's, together with a transition-metal activated NaBH4 reduction of the phenylacetonitrile. |
||||||||
sunlight (Hive Bee) 09-05-01 12:07 No 210319 |
Re: New route to PEAs? | |||||||
What about de procedure of ethylchlroformate+KCN to give de acetonitrile from the aldehyde ? it could be very useful for 2CH or mescaline if the nitrile is easily reduced with NaBH4 and NiCl2 or others. |
||||||||
Rhodium (Chief Bee) 09-05-01 12:46 No 210339 |
Re: New route to PEAs? | |||||||
The reference is Archiv der Pharmazie 283, 190 (1950), but neither Sonson or myself have ready access to that journal. Anyone? |
||||||||
psycosmo (Stranger) 09-07-01 02:18 No 210946 |
Re: New route to PEAs? | |||||||
Thre have got to be easier, more OTC methods of producing phethylamines from benzene than the standard benzyl cyanide --->reduced to PEA? Is it at all possible to introduce an alkylamino group directly using a haloalkylamine (?), or to form styrene and introudce an amino group to that. In that respect could a route be derived from the rhodium complex addition of secondary amines to styrenes? This method is described oN: http://www.ifok.uni-rostock.de/e/Science/Projects/atilla Might be a fun thing to do with some mothballs that have been treated with NaOCH3 or some such compund.. |
||||||||
obituary (Hive Addict) 09-07-01 04:35 No 210973 |
Re: New route to PEAs? | |||||||
wasn't there something about the addition of IN3 (halogen azides) to alkenes? it will give the respective azide which can be reduced ( the you have to get rid of the halogen-- obit thinks it tacks on with the azide, or maybe it just forms an acid(?)) comments? |
||||||||
Rhodium (Chief Bee) 09-07-01 12:08 No 211061 |
Re: New route to PEAs? (Rated as: good read) |
|||||||
Psycosmo: The method in the link only works with secondary amines (and preferably with cyclic ones such as piperidines and pyrrolidines). Obituary: halogen azides are spontaneously explosive, and nobody I know would even consider using them. Sonson/Sunlight: The chloroformate ref has been retrieved, and it reads as follows: 0.1 mol of aldehyde in ether is treated with 0.125 mole of ethyl chloroformate and a solution of 9.8g of KCN and 31g MgSO4*7H2O in 50ml water. The mixture is stirred/shaken [geschüttelt] vigorously with cooling in ice for 3h. After that the etheral layer is separated, and washed with water and then with 10% Na2CO3 until no more chloride could be detected in the washings. The etheral solution was washed with 30% NaHSO3, and then with water to remove the excess sulfite. After thorough drying over CaCl2 and evaporating the ether, the O-carbethoxymandelonitrile is gotten in a good yield, pure enough for the next step. 0.1 mole of O-carbethoxymandelonitrile is dissolved in benzene together with 1.5g palladium black, and heated to boiling, and hydrogen gas is bubbled through the benzene solution until the excess hydrogen flowing out of the reaction mixture is free of carbon dioxide. The resulting solution was filtered, washed with dilute HCl [to remove any nitrile over-reduced to the phenethylamine] and dried over CaCl2. After evaporation of the solvent, the desired benzyl cyanide is purified by distillation or recrystallization. There is also a table over boiling and melting points of the prepared benzyl cyanides. The yields are between 70-90% depending on the starting aldehyde (the less substituted, the better the yield). Ref: Archiv der Pharmazie 283, 190 (1950) I think that NaBH4 reduction of the aldehyde to the alcohol, shaking with HX(aq) to the benzyl halide, and SN2 with cyanide will give as high yields with a lot less work. |
||||||||
Rhodium (Chief Bee) 09-07-01 12:29 No 211063 |
Re: New route to PEAs? (Rated as: excellent) |
|||||||
A Rapid, Convenient Preparative Procedure for Phenethylamines Edgar F. Kiefer, J Med Chem 15(2), 214 (1972) In view of the very broad pharmacological utility of substituted 2-phenylethylamines, we wish to contribute a synthetic procedure which, because of its versatility and convenience, may find considerable use. Although based entirely on standard synthetic methods, the overall scheme is specifically tailored to the properties of the benzylic intermediates involved, and eliminates the need for isolation of intermediates and other time-consuming operations. The procedure is described for the p-methoxy derivative; it is also applicable without substantive modification to other ring alkoxy-, alkyl-, and halogen-substituted phenethylamines. Experimental Section 4-Methoxyphenylethylamine Hydrochloride. p-Anisyl alcohol (100 g, 0.725 mole) was shaken with 500 ml of concd HCl for 2 min. The org phase was washed with 1120, 5% NaHCO3 and H2O then added over 40 min to a stirred slurry of 49 g (1.0 mole) of NaCN in 400 ml of DMSO [1], with ice-water cooling to maintain the temp at 35-40°. After addn was complete, the cooling bath was removed, the mixt was stirred for 90 min and then added to 300 ml of H10, and the small upper phase sepd. The aq DMSO layer was extd with two 100-ml portions of Et2O which were combined with the product layer, and the whole was washed once with H20 and dried (MgSO4). A dry flask was charged with ca. 600 ml of abs Et2O and chilled in ice as 80 g (0.6 mole) of anhyd AlCl3 was added portionwise, followed by 23 g (0.6 mole) of LAH (LAH alone and other metal hydride reagents are unsatisfactory for the reduction of benzylic nitriles to amines) [2]. The dried Et2O soln of crude p-methoxyphenylacetonitrile was added at such a rate as to maintain gentle reflux without external heat (ca. 1 hr). The mixt was stirred for 2 hr, then chilled in ice, and treated dropwise with 25 ml of H2O followed by 250 ml of 20% of aq NaOH, with periodic addn of Et2O through the condenser to replenish losses and facilitate stirring. The resulting voluminous, granular ppt of NaCl and LiCl and aluminate was removed by filtration, washed well with Et2O and discarded. The filtrate was mixed with one-third its vol of abs EtOH and 60 ml of coned HCl was added slowly with continuous swirling and ice cooling. After chilling to 0°, the cryst amine hydrochloride was collected, 101 g, mp 212-214°C. The overall yield was 75% from anisyl alcohol. The hydrochloride may be recrystd from Et2O-EtOH or i-PrOH. N-Methyl-p-methoxyphenylethylamine Hydrochloride. p-Methoxyphenethylamine, generated from 100 g (0.536 mole) of the hydrochloride by stirring with coned aq NaOH, was treated with 100 ml of PhH and 70 g (0.66 mole) of PhCHO. A mildly exothermic reaction began at once. The mixt was heated under reflux until no more H2O was present in the condensate (ca. 1 hr), then, without cooling, an attached Dean-Stark trap was removed and a soln of 82 g (0.65 mole) of Me2SO4 [3] in 200 ml of PhH was added through the condenser at such a rate as to maintain reflux (15 min). The 2-phase mixt was heated for 90 min on the steam bath, cooled slightly, treated with 200 ml of H20, and heated for an addn 20 min. After cooling in ice, the aq layer was washed twice with Et2O to remove unreacted PhCHO and made strongly basic with 50% aq NaOH. Two Et2O exts of the basic aq phase were added to the amine layer which sepd, and the resulting soln was evacd at the aspirator for 30 min, leaving 90 g (102%) of crude N-methyl-p-methoxyphenethylamine. This material was dissolved in 500 ml of 20% abs EtOH-Et20 and treated with 50 ml of coned HCl with swirling and cooling to yield the white, cryst hydrochloride, which was washed thoroughly with ice-cold 20% EtOH-Et20 and dried, mp 185.5-186.5°C. The yield was 83 g (77%). References (1) R. A. Smiley and C. Arnold, J. Org. Chem., 25, 257 (1960). (2) R. F. Nystrom, J. Amer. Chem. Soc., 77, 2544 (1955). (3) J. J. Lucier, A. D. Harris, and P. S. Korosec, Org. Syn., 44, 72 (1964). Blame Omnipage for any typos. I don't really get the reaction mechanism in the last step where they monomethylate the phenethylamine. They make the benzaldehyde/phenethylamine imine, methylate that to get the "quaternary imine" (is that an enamine?) which is then hydrolyzed back to benzaldehyde and N-methyl phenethylamine? If so, then this could be an easy general method for monomethylating amphetamines to methamphetamines (or MDA analogs to MDMA derivatives). |
||||||||
Antoncho (Official Hive Translator) 09-07-01 13:58 No 211080 |
Re: New route to PEAs? | |||||||
|
||||||||
Rhodium (Chief Bee) 09-07-01 14:54 No 211093 |
Re: New route to PEAs? | |||||||
Antoncho: I believe you are mistaking nitrogen triiodide (NI3, prepared from ammonia and iodine) for Iodine Azide (IN3, which is discussed above), right? |
||||||||
Antoncho (Official Hive Translator) 09-07-01 18:57 No 211145 |
Re: New route to PEAs? | |||||||
Antoncho P.S. as for the rxn mech. - i believe that someone on HyperLab has made meth from amph this way once - a long time ago. i don't know what aldehyde he used for forming Shiff's base but am pretty sure it was smth even simpler than benzaldehyde. |
||||||||
Rhodium (Chief Bee) 09-07-01 19:27 No 211154 |
Re: New route to PEAs? | |||||||
Do you or anyone else know the reaction mechanism for it? References where I can look it up? |
||||||||
Lilienthal (Moderator) 09-07-01 19:46 No 211160 |
Re: New route to PEAs? | |||||||
I have some, will post them later. But you are right about the mechanism. |
||||||||
Osmium (Stoni's sexual toy) 09-07-01 20:27 No 211169 |
Re: New route to PEAs? | |||||||
Now that's a really old reaction, I'm surprised you don't know this one Rhodium. |
||||||||
Rhodium (Chief Bee) 09-08-01 01:59 No 211244 |
Re: New route to PEAs? | |||||||
I haven't learned about it anywhere (as in here or in school), I just guessed the rxn mechanism. If it is this easy to monomethylate amphetamine, why aren't people using that method all the time time to make meth from amphetamines? Or do the yields suffer when the substrate is a secondary amine? I thought the only way was to make the formyl amide and then reduce it with LAH... Or a HCHO/HCOOH reductive amination (Eschweiler-Clarke), but that would easily form the tertiary amine. |
||||||||
psycosmo (Newbee) 09-10-01 02:59 No 211749 |
Re: New route to PEAs? | |||||||
OK im sure this wont work because its so obvious and not metnioned anywhere, but it looks too good not to mention. Basically it adopts the benzylamine synth from tolulene for ethylbenzene what if one took benzene and reacted it with ethylene to get ethylbenze, then adopted a bezyl chloride from tolune proceedure to halogenate it, and then adopted a non-cyanide using benzylamine synthesis (Ive seen references to something called a Gabriel Synth that use "alchoholic ammonia") but I cant find detailed enough info on benzylamine synthesis (did a google search). Anyway I dont see any reason why this wouldnt work. |
||||||||
Sonson (Stranger / Eraser) 09-10-01 07:18 No 211809 |
Re: New route to PEAs? | |||||||
Ho! I found this in pihkal last night...reduction of acetonitriles to amines with NaBH4 and TFA! A solution of 4.7 g 3,5-dimethoxy-4-(n)-propoxyphenylacetonitrile in 20 mL THF was treated with 2.4 g powdered sodium borohydride. To this well-stirred suspension there was added, dropwise, 1.5 mL trifluoroacetic acid. There was a vigorous gas evolution from the exothermic reaction. Stirring was continued for 1 h, then all was poured into 300 mL H2O. This was acidified cautiously with dilute H2SO4, and washed with 2x75 mL CH2Cl2. The aqueous phase was made basic with dilute NaOH, extracted with 2x75 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue was distilled at 115-125 °C at 0.3 mm/Hg to give 1.5 mL of a colorless oil which upon dissolving in 5 mL IPA, neutralizing with 27 drops concentrated HCl, and dilution with 25 mL anhydrous Et2O yielded 1.5 g 3,5-dimethoxy-4-(n)-propoxyphenethylamine hydrochloride (P) as spectacular white crystals. The catalytic hydrogenation process for reducing the nitrile (see under E) also succeeded with this material. The mp was 170-172 °C. Anal. (C13H22ClNO3) C,H,N. Simple eh? |
||||||||
Rhodium (Chief Bee) 09-10-01 10:06 No 211827 |
Re: New route to PEAs? | |||||||
Sonson: Very simple, but I feel the yields are a bit on the low side. Perhaps the NiCl2/NaBH4 route would be higher yielding (or maybe it is jst due to the substrate). I wish Pihkal had references for the reactions used... Psycosmo: If ethylbenzene was halogenated, the product would be the 1-phenethylhalide (with the halogen on the same carbon as the benzene ring), not the 2-phenethylhalide we would like to have. But the Gabriel synthesis (Potassium phtalimide + alkyl halide is nevertheless very interesting to produce amines, from for example bromosafrole, it should be MUCH better than trying to use the delephine reaction). |
||||||||
Sonson (Stranger / Eraser) 09-10-01 12:19 No 211861 |
Re: New route to PEAs? | |||||||
Maybe...but Shugin doesnt say how much product that resultet before the distillationstep. This operation can be very wasteful as we all know...I've seen refs. were yields are in the 70%-range using TFA and 70-80% using I2 instead. I'll get these for you all... |
||||||||
psycosmo (Newbee) 09-11-01 04:14 No 211961 |
Re: New route to PEAs? | |||||||
Not to keep on a dead issue but why wouldn't adding a halogen to end carbon of ethylbenzene be the same as adding it to end carbon of methylbenzene (tolulne)? Perhaps I should have mentioned that by "halogenate" I meant react with HCl in the Presence of AlCl3 as per described in the clorination of tolulene. Or would we still end up with the halogen in the wrong place? |
||||||||
Rhodium (Chief Bee) 09-11-01 05:46 No 211978 |
Re: New route to PEAs? | |||||||
It will still add in "the wrong place". The kind of halogenation you are talking about prefers placing the halogen at the benzylic carbon (the one next to the phenyl group) regardless if it is toluene, ethylbenzene or pentylbenzene. It is only in the case of toluene the halogen happens to be on the end of the side chain, as there is only one carbon for it to attach to. |
||||||||
psycosmo (Newbee) 09-17-01 01:47 No 214202 |
Re: New route to PEAs? | |||||||
OK, how 'bout this: Aminate 1,2 dibromomethane to make 2-bromoethylamine, and then use standard aromatic alkylation prcedures using alkyl halides? Will the amine on the other end of the molcule create problems? Post No 192074 talks about using dibromomethane, but it seems that polymerization is a problem. Will this avoid that problem? |
||||||||
Rhodium (Chief Bee) 09-17-01 22:49 No 214507 |
Re: New route to PEAs? | |||||||
Polymerization would be almost the only reaction occurring. One way would be to use the acetylated 2-bromoethylamine, and an established route to amphetamines is the use of trifluoroacetylated alanine in the friedel-crafts acylation of aromatics, followed by reduction and deprotection. |
||||||||
psycosmo (Newbee) 09-18-01 05:06 No 214609 |
Re: New route to PEAs? | |||||||
maybe try to add chloroacetaldehyde to the benzene ring and then do a p2p style reductive amination to get the phenethylamine?? It would be so nice if there could just be a nice, easy, OTC way to get PEA..... ::sigh:: |
||||||||
Rhodium (Chief Bee) 09-18-01 11:17 No 214718 |
Re: New route to PEAs? | |||||||
Are you talking friedel-crafts? I believe aldehydes add at least as easily as alkyl chlorides to benzene rings under those condintions, so you would get a real mixture of products. |
||||||||
Rhodium (Chief Bee) 05-16-04 15:21 No 507503 |
Nitriles and Amides to Amines with n-Bu4BH4 (Rated as: excellent) |
|||||||
Reduction of Nitriles and Amides to Amines with Tetrabutylammonium Borohydride In Dichloromethane T. Wakamatsu, H. Inaki, A. Ogawa, M. Watanabe, Y. Ban Heterocycles 14(10), 1437-1440 (1980) (https://www.rhodium.ws/chemistry/amide-nitrile2amine.bu4bh4.html) Abstract The reduction of nitriles and amides to the corresponding amines with tetra-n-butylammonium borohydride in dichloromethane has been reported, in which the other functional groups such as ester, nitro, and halogen attached to the aromatic ring are not affected. The Hive - Clandestine Chemists Without Borders |
||||||||