Hi, I have an indole related question, so I will make my first ever tryptamine forum thread.
First of all, what is a Mannich salt? Is it the same as a Mannih base? I cannot locate any data on Google with the term "mannich salt" and it isnt in any chemistry dictionaries I have, nor in March's 5th under that term. But
The Chemistry of Mind Altering Drugs, pg. 276 refers to a compound as a mannich "salt" and I dont know what that is.
Basically, I don't have a real question, but rather a statement that I am confused. I don't quite understand how this works or what is going on. here is the excerpt:
"In 1981, Oppolzer reported an elegant synthesis of lysergic acid, in which the C and D rings are formed in a single intramolecular process. The phosphonium bromide [6-20] could be made in near quantitative yield, and bicycloheptene [6-21] in about 60% yield from readily available materials. A Wittig reaction between these two provided [6-22] after removal of the tosyl protecting group, in 62% yield."
That's fine and dandy, I understand
all of that just fine, its the next part:
"Condensing the Mannich salt of [6-22] with nitromethane and reduction with TiCl3 gave [6-23] in an overal yield of about 35%...."
It goes on further but I understand all of that too.
What I
do not get at all is what the hell is happening in this last part? The whole bicyclo and ylid portion of the molecule is irrelevant, so dont worry about that, This step involves another portion of the molecule seperate from all that.
What they show in the diagram is the 3-position of indole getting alkylated, and having a R-CH2-CH=N-O-CH3 form off the 3-position in indole, where R = indole. What I do not get is where the oxygen comes from, where this second carbon comes from, and how the hell the imine is formed. Basically I just cant put together one single part of this step with the picture provided.
I looked up the mannich reaction and it involves addition of ammonium salts to formaldehyde, forming H2N-CH2-OH, which reacts with compounds containing "an active hydrogen" and the example is with acetic esters at the terminal carbon.
Well I assume that the 3-position of indole serves as the "active hydrogen" spot, but where does the second carbon come from? H2N-CH2-OH should react with indole, forming R-CH2-NH2, not the R-CH2-CH system shown. I dont understand.
Is the oxygen present in the =N-O-CH3 a typo? I wouldnt think so, but it makes no mention kater in the excerpt of removing this methoxy group and methylating the nitrogen to make lysergic acid. I dont see how the reduction with TiCl3 fits in, and how this imine is formed.
Pleeeeeease help?
anyone who can discuss this is very much welcome to, and I especially invite answers from Rhodium (because I know you have this book and can look up the pictures) from Osmium because you seem to have experience with every damn procedure under the sun, and Lilienthal because I
know you know a lot about tryptamine chemistry, and hopefully are familiar with this synthesis. Any help would mean a lot to me.
This is the one and only portion of this synthesis that I do not understand as far as I can tell. I struggled a bit trying to figure out how the hell they created the bicyclo/norbornene compound with a carboxyl and a formyl off the same carbon, but the answer was obvious after I got stuck and admitted that I didnt have the skill to synthesize bicyclics in my head: The opposite of what happens next: the retro-diels-alder that extrudes cyclopentadiene. Obviously reacting methyl 2-formylacrylate with cyclopentadiene would form this compound, as it is the opposite of the "retro reaction" that produces the equivalent to this.
The only other mystery is how they prepared the 4-bromomethyl derivative of indole to make the ylide for the Wittig reaction, but Im sure I'll find out all in due time. I wonder about simply bromomethylating indole, but I doubt its this simple, and I cant predict where the bromomethyl would add. Arg. All in due time all in due time.......
I can assure you that I have searched google for a variety of things related to these compounds and for Oppolzers synthesis as well, Google doesnt know much about it. I should try Sirus next.
Please help with the Mannich part. Thanks again.
PrimoPyro