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Author Topic: Mannich reaction??  (Read 146 times)

2bfrank

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Mannich reaction??
« on: October 12, 2009, 12:00:09 PM »
Been flicking through a medicinal chem book I got on file, and was looking at the section on Mannich reactions, and this one in particular was for Dimethylcathinone/Metamfepramone
see here..http://en.wikipedia.org/wiki/Dimethylcathinone
and for those who aren't familiar, or like me, forget, and need constant reminding etc
see for Mannich reaction...http://en.wikipedia.org/wiki/Mannich_reaction

so this prep in this book(not bad book either) seepage 188 http://www.4shared.com/file/140005493/3fc808b4/_2__8122415393_Medicinal_Chemistry.html
 if interested, anyway, they use acetephenone, paraformaldehyde, dimethylamine HCl, as the main players, and produce the Dimethylcathinone, So big fucking deal you might be thinking, yeah yeah yeah, a Mannich reaction with aldehyde, ketone and amine, so WTF Well I always assumed that paraformaldehyde would react with the di-methylamine,, with loss of H2O, hence producing a charged imine, and has a very electrodeficient carbon opposit the charged Nitrogen, and the Ketone, being acetephenone, goes on to form a resonating enol, that ends up attacking the imine, therefore the addition of an extra carbon, a methylene bridge, and the amine/dimethyl etc on the terminal carbon, and this doesn't appear to of occured in this reaction I gave the link for....
Its almost as if the ketone, has turned to an enol, and itself attacking the paraformedhyde, this loosing water, thus forming a Phenyl-prop-1-ene-3-one ( know that that is bullshit naming, but basically it being a possible 3- phenyl-1-propene-3-one, that the nitrogen base, and its lone pair have attacked the carbon alpha to the ketone, hence the dimethylamino is sitting on a secondary carbon rather than the primary carbon, which I thought would of result if indeed the enol attacked the imine, in the traditional sence of a mannich reaction,,This appears unlikely, the carbon alpha to the carbonyl is slightly electro deficient compared to the terminal carbon, that has 2 hydrogens atached, and the carbonyl could also be extracting electron density of the secondary carbon, the one that  has ended up with the amine, So If my thinking is correct, quite doubtful, but has been known to happen, then methylamine could be substituted and a very useful molecule could be obtained, a molecule that could be changed somewhat, or if the proposed mechanism is correct, then it opens possibilities, It may well be that the book is wrong, but interesting to say the least.
what I do not understand, nor does a peer, that weve discussed this with, is why present a mannich reaction resuliting in the amine not ending up on the terminal carbon....Thoughts appreciated..

zzhuchila_clocker

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Re: Mannich reaction??
« Reply #1 on: October 12, 2009, 03:00:44 PM »
That is definitely a mistake in the book. Addition of dimethyamine to phenylvinylketone PhCOCH=CH2 would also lead to same product PhCOCH2CH2NMe2, called michael addition. b-carbon is more electron-deficient here compared to alpha because of resonance
PhCOCH=CH2  <-->   PhC(O-)=CH-CH2+ .  I can not propose any mechanism of how the cathinone derivative can be formed. If it worked, it should have been definitely known
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zajcek01

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Re: Mannich reaction??
« Reply #2 on: October 12, 2009, 03:08:22 PM »
I'm just a dreamer.......

2bfrank

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Re: Mannich reaction??
« Reply #3 on: October 13, 2009, 12:48:32 AM »
Thanks guys, I did think it unlikely, and Forgot the unforgivible in OCHEM- dare I speak its name- Resonance - but for completion I will compare procedures, and then no doubt drop it..

POSEIDON

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Re: Mannich reaction??
« Reply #4 on: October 14, 2009, 03:12:27 AM »
swi2bf look this link of org syn http://www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0305

swip thinks  is an error in the book 
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heisenberg

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Re: Mannich reaction??
« Reply #5 on: June 26, 2010, 04:35:56 PM »
Dimethylcathinone could be made by the mannich reaction of dimethylamine, formaldehyde, and propiophenone.

Quote from: POSEIDON on October 14, 2009, 03:12:27 AM
swi2bf look this link of org syn http://www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0305

swip thinks  is an error in the book 

That procedure looks all correct to me...
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Naf1

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Re: Mannich reaction??
« Reply #6 on: June 26, 2010, 09:06:07 PM »
Quote
That procedure looks all correct to me...

Yes the procedure you quoted is correct, this is the one ziggy and zhuchila were talking about though;

heisenberg

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Re: Mannich reaction??
« Reply #7 on: June 27, 2010, 03:25:24 PM »
Ah, I thought I must have missed something.
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Sedit

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Re: Mannich reaction??
« Reply #8 on: June 27, 2010, 08:44:23 PM »
From the looks of the mechanism that the Mannich reaction proceeds why use Dimethylamine exactly? Wouldn't Methylamine yeild a more interesting product?
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heisenberg

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Re: Mannich reaction??
« Reply #9 on: June 27, 2010, 08:58:07 PM »
Quote from: Sedit on June 27, 2010, 08:44:23 PM
From the looks of the mechanism that the Mannich reaction proceeds why use Dimethylamine exactly? Wouldn't Methylamine yeild a more interesting product?

Methylamine could react in a second mannich immediately after the first. I think that it's possible to do mannich's on primary amines, but they're more problematic than secondary amines which can only react once.
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2bfrank

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Re: Mannich reaction??
« Reply #10 on: June 28, 2010, 12:50:22 AM »
This really should of just been a quick question is the short question thread regarding, THis is obviously a mistake yeah, or am I missing something, rather than a thread on its own. Not thinking to clearly back then..

Naf1

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Re: Mannich reaction??
« Reply #11 on: June 28, 2010, 01:20:37 AM »
Zhuchila did answer it spot on (like usual), straight away though;

Quote
That is definitely a mistake in the book. Addition of dimethyamine to phenylvinylketone PhCOCH=CH2 would also lead to same product PhCOCH2CH2NMe2, called michael addition. b-carbon is more electron-deficient here compared to alpha because of resonance
PhCOCH=CH2  <-->   PhC(O-)=CH-CH2+ .  I can not propose any mechanism of how the cathinone derivative can be formed. If it worked, it should have been definitely known

The technique used generally in the lab would be seen here and is analogous with the general procedure for cathinones. But as stated propiophenone could also be used in a Mannich reaction;

Quote
Cathinone: An Investigation of Several N-Alkyl and Methylenedioxy-Substituted Analogs
TERRY A. DAL CASON,* RICHARD YOUNG† AND RICHARD A. GLENNON†
Pharmacology Biochemistry and Behavior, Vol. 58, No. 4, pp. 1109–1116, 1997

(+/-)N-Monoethylcathinone (N-Et CAT), (+/-)N-mono-propylcathinone (N-Pr CAT), and (+/-) N, N-dimethylcathinone (Di Me CAT) were prepared as their hydrochloride salts from 2-bromopropiophenone (Aldrich Chemical Co., Milwaukee,WI) by reaction with the appropriate aqueous amine (free base) in a 1 to 2 molar ratio. A general procedure, as adapted from the literature (23), will suffice. Previously chilled
(58C) bromopropiophenone (0.42 mol) was added in a dropwise manner over a 30-min period to a stirred solution of the aqueous amine (free base, 0.85 mol) immersed in an ice-salt (288C) bath. The reaction mixture was stirred for 2 h and then allowed to come to room temperature. The mixture was extracted with tap water (4 3 100 ml) to remove any free amine or amine salt. An additional quantity of water (100 ml) and sufficient hydrochloric acid were added to the washed reaction mixture to achieve pH 2. The solution was reextracted with chloroform (4 3 100 ml) to remove any unreacted starting materials. Dilute cold sodium hydroxide solution was added to ad-just the pH to 9–10; the reaction mixture was extracted with chloroform (4 3 50 ml) and the solution was filtered through anhydrous sodium sulfate. The hydrochloride salt was formed by the addition of a solution of HCl gas in 2-propanol (4.5 N) and the reaction mixture was evaporated to dryness on a steam bath. The recovered solid was dissolved in hot 2-propanol
followed by the careful addition of diethyl ether until turbidity was noted. The next day, after having been stored in a freezer overnight, the solution was filtered, and the crystalline material was collected and dried under vacuum for at least 2 days. The melting points (Hoover Unimelt apparatus) were found to be: N-Et CAT, mp 186–1888C (mp 1838C) (23), (mp 1828C) (26); N-Pr CAT, mp 180–182.58C, (mp 1808C) (23), (mp 1828C) (26); Di Me CAT, mp 206–206.58C (mp 202–
2048C) (28). S(2)-N,N-Dimethylcathinone HCl, mp 197.5– 2008C; (a) 5 252.5 (H2O, 1%), (mp 197–1998C; (a) 5 252.5
(H2O)) (32) was prepared from 1R,2S-N-methylephedrine HCl (Aldrich) by oxidation with sodium dichromate/sulfuric acid in a manner analogous to that previously described for the preparation of S(2)methcathinone HCl (18).
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