PrimoPyro (Hive Prodigy)
10-11-02 16:43
No 367310
      Cocaine Analog WIN-35,428 Synthesis Idea  Bookmark   



Starting from plain tropinone, Grignard addition of p-fluorophenylmagnesium bromide to tropinone in THF gives the tertiary alcohol pictured in the top center. This is dehydrated with KHSO4 to the alkene in the top right.

Then the alkene is hydroborated to get anti-Markovnikov addition, which is reacted with N-chlorodiethylamine in one pot to get the anti-Markovnikov chloroalkane, which is then subjected to reaction with potassium cyanide to get the nitrile.

Alcoholysis is performed on the nitrile in methanol to get the methyl ester, WIN-35,428.

Questions that are important:

My book on organometallics says that hydroboration is stereoselective to "cis addition" I assume this is important since we need to get the correct stereoisomer of WIN-35,428 for it to be worth a damn.

Also, by what mechanism does the reaction with N-chlorodiethylamine proceed? Does it switch the chirality of the stereocenter, or does it cause racemization? (yuk)

And again, would addition of -CN be SN1 or SN2? We may be switching the chiral center back and forth a couple times, and Im not familiar (yet) with this kind of stuff, so I'd rather ask for help than risk an incorrect guess as to which isomers are formed and how they survive the reactions.

So, what is the consensus?

PrimoPyro

Firm supporter of the "Purge The Couch!" movement. Vote for the purge today.
 
 
 
 
    Rhodium
(Chief Bee)
10-11-02 16:58
No 367315
      Cis is the desired isomer, but remember that the ...  Bookmark   

Cis is the desired isomer, but remember that the alkene you are hydroborating is a racemic mixture - the double bond can be either to the right or left of the phenyl group, so after hydroboration you still have at least two stereoisomers in the mix.

The alkylborane and N-chlorodiethylamine will form the diethylaminoalkane. I don't see how this could be turned into a cyanide without first quaternizing it with methyl iodide, in which case the R-Et2Me+I- reacts with CN- in a normal SN2 fashion, with Et2NMe as leaving group.
 
 
 
 
    PrimoPyro
(Hive Prodigy)
10-11-02 17:05
No 367317
      Different Results  Bookmark   

Page 60 of Organometallics, A Concise Introduction shows a diagram much like the Grignard Reaction products diagram you once posted, but for hydroborated products. It shows RCH2CH2BR'2 + Et2NCl ---> RCH2CH2Cl

That is what I was going off of for this. I dont have any more info on it (yet) that's why I asked about it. Are we talking about the same thing here or something different?

PrimoPyro

Firm supporter of the "Purge The Couch!" movement. Vote for the purge today.
 
 
 
 
    Rhodium
(Chief Bee)
10-11-02 17:12
No 367320
      Okay, I guessed the mechanism wrong (uh, as in ...  Bookmark   

Okay, I guessed the mechanism wrong (uh, as in not reading your post closely enough) - it seems like Et2NCl transfers a chlorine to the alkylborane, rather than a diethylamino group, right?

If so, then there are many simpler reagents available to halogenate organoboranes.

I don't know about the stereochemistry of organoborane substitution, but the second halide to cyanide substitution should be SN2.
 
 
 
 
    PrimoPyro
(Hive Prodigy)
10-11-02 17:19
No 367325
      Hm ok  Bookmark   

So that will invert the chiral center, meaning we will want to have it inverted again prior (so the result is that no inversion takes place regarding the final nitrile).

And could you elaborate and tell me of some of these simpler reagents for halogenating organoboranes? I did not like needing the use of Et2NCl. Other options welcomed.

PrimoPyro

Firm supporter of the "Purge The Couch!" movement. Vote for the purge today.
 
 
 
 
    Rhodium
(Chief Bee)
10-11-02 22:26
No 367409
      Organoboranes -> Alkylbromides The ...  Bookmark   

Organoboranes -> Alkylbromides

The organoborane (5 mmol) in THF was cooled to 0C. Water (10 mL) was added and the reaction mixture shielded from light. Bromine (5 mmol) dissolved in THF (10 mL) at 0C was added to the organoborane and the mixture stirred for 30 min. Ether (30 mL) was added to extract the product. The ether layer was washed with two 30-mL portions of water and dried over anhydrous MgSO4 and the solvent was removed to give the crude alkyl bromide, yields 90-95%.

Ref: GW Kabalka, J Org Chem 46(15) 3113-3115 (1981)

As an added bonus, the authors postulate that the borane -> bromide reaction occurs through an SN2 pathway.
 
 
 
 
    SPISSHAK
(Hive Bee)
10-12-02 14:35
No 367660
      Just go the easy route  Bookmark   

Cocaine is cheap and easy to get, just get a kilo for 10 G's , only $10 a gram, and use that as a staring point.
Occums razor should be applied here.
 
 
 
 
    Rhodium
(Chief Bee)
10-12-02 20:00
No 367705
      Occam's razor may yield different results  Bookmark   

Spisshak: I don't know about your situation, but it would be way easier, cheaper and take shorter time for me to synthesize 10 grams of cocaine from chemicals just lying around than to try to purchase it on the black market (taking into account that black market cocaine is impure, diluted with non-cocaine things, as well as the people I'd finally find selling any would rip me off). I don't know a single person who uses cocaine, and very few who are regular drinkers. Most of my friends are very health-conscious, only dabbling into synthetic drugs now and then (with the exception of cannabis-derived preparations).
 
 
 
 
    PrimoPyro
(Hive Prodigy)
10-13-02 03:20
No 367790
      Jesus  Bookmark   


Just go the easy route   Bookmark  Reply    

Cocaine is cheap and easy to get, just get a kilo for 10 G's , only $10 a gram, and use that as a staring point.
Occums razor should be applied here




How many fucking times do I have to say this in different words? That is not the damn point. What is the purpose of this bullitin board? Hmm? The harvest, production, and distribution of information regarding chemical syntheses is what it's supposed to be about.

I somewhat agree with you though. Purchasing a prebuilt molecule of cocaine to work on as a substrate may be a better choice, but only for some. I for one would much rather spend vastly less money and just perform a near-total synthesis of such a molecule than to buy it for the outrageous prices on the street. And scale is an issue. To get a fairly decent price of cocaine you have to buy a shitload. What if I didn't want a shitload?

It all boils down to opinion of "what is better" and frankly Im sick of my posts about a synthesis being passed off as "just buy it". Its not so much the words, because facts are facts, its mostly the attitude that pisses me off.

"Don't think. We don't need this, we never will. Dont bother thinking about this type stuff. Just buy it."

Fuck that.

PrimoPyro


Firm supporter of the "Purge The Couch!" movement. Vote for the purge today.
 
 
 
 
    flipper
(Hive Bee)
10-17-02 23:53
No 369696
      well  Bookmark   

So somebody figured out if it works. 
 
 
 
 
    PrimoPyro
(Hive Prodigy)
10-18-02 00:19
No 369707
      Doubt it  Bookmark   

No, my pissy rant seems to have killed any discussion that might have arisen. frown

I doubt this is something anyone would ever try anytime soon anyway. frown

PrimoPyro
 
 
 
 
    slappy
(Hive Bee)
10-18-02 07:26
No 369840
      Idea  Bookmark   

I think that the logical precursor here is Methyl Ecogoine. 1,4-Conjugate addition (Micheal) with (4-Fluorophenyl)2CuCNLi2.
 
 
 
 
    SPISSHAK
(Hive Bee)
10-18-02 09:53
No 369884
      To Rhodium  Bookmark   

yeah in Europa It's hard to get good coke.
I understand, I used to deal the fuck out of it and one of my custies was vladdimier from switzerland who says the purity of coke there just sucks.
Over here in the land of the oppresed it's cheap and easy to get and what I get is about %70 pure so I try not to fuck with conventions when I got it good
wink
But I still think that meta-hydroxy cocaine would be the easiest analog of the greatest potency of the natural cocaine analouges.
As detailed in the paper on your page it binds to dopamine receptors really well and is easily prepared from aspirin chloride(acetylsalicyloyl chloride), and methyl ecgonine  which is a transesterification product of cocaine and methanol in (anyhydrous) basic conditions,in chloroform with a mixture of calcium carbonate and calcium oxide (to nuetralize acids formed and absorb water).