I have come across this reaction and decided to open the discussion
Here is an example of alkylation to JWH-018, 1-pentyl-3-(1-naphthoyl)indole, MW 341.4
To a 250ml 3 neck RBF fitted with thermometer, condenser and a stir bar there is added 3-(1-naphthoyl)indole (3g, 11mmol) followed by dry DMF 50ml. Potassium hydroxide flakes (1.5g, 27.5mmol 1.5eq.) were added in one portion and the setup purged with butane. The flask was heated to 60-70 degrees C on a water bath for 20 minutes with stirring. A green solution with ppt is obtained. After this time, 1-bromopentane (4.3g, 28.6mmol) was added in one portion via glass syringe. There is an immediate color change to red and the flask is heated at an internal temp of 60-65 C for 3 hours. KBr ppts in the first few minutes after addition of the alkyl halide. It is then cooled to RT and diluted with 150ml H2O, and extracted with DCM 3x 40ml. The organics are washed with water 3 times then the solvent is evaporated. There is excess bromopentane as noticed by the smell so it is removed under vacuum in a hot water bath. 3g of amber oil was obtained (8.8mmol, 80% yield) The amber oil that remains is the product. It is a pain to get it to crystallize. Only after 1 month in the refrigerator did crystals begin to form. By covering them with a small amount of IPA cleaned them up and caused all of the oil to crystallize. Once you have a seed crystal the oil can be directly crystallized after alkylation, but I have had no luck getting it to crystallize right after without the seed or with ethanol. The obtained material is completely melted by 61 C, lit Mp is 60-62 C.
The product is fucking active and is obtained as beige to yellow slightly gummy crystals. It would be best to straight chromotograph the oil but not everyone can do that.
Huffman JW, Mabon R, Wu MJ, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR.
“3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB(1) cannabinoid receptor”.
Bioorg Med Chem. 2003 Feb 22;11(4):539-49.
So many questions come up, I have to go over notes to include them all. I hope these issues come along as discussion progresses. One of them I have posted recently at the JWH-018 thread, which is, what is the safe(optimal) temperature to evaporate residual water, solvent and bromopentane? I have read elsewhere and on the literature DMSO being used instead, and I have tried both but crystallization was not successful so I can't determine which one is best and I can think of no way to determine this besides running a cavia sapiens operation so it's unavailable, unreliable and we are down to serious science, but rumor is that DMF is better because of the reason. And to be fair, I wasn't the one who heard this rumor. Someone I know did.
So this reaction states that dry DMF is used. Does this impact on the yield? Should KOH be dried as well? Can K2CO3 be used successfully?
Alkylations described by Billy Dampier (current hero, savior and inspiration
Thanks Billy!) use NaH as reducing agent as is widely found in the literature, and it certainly requires absolutely dry conditions unless one's intention is to destroy evidence via undocumented but widely known oxidation procedures but adb and 5cl precursor sellers have =>answered<= (I can't remember who asked, citation needed) that DMF does not necessarily need to be dried for the reaction in question, and those are corresponding alkylations, so are the sellers wrong, or is dry environment unnecessary in that case only? Would it, although unnecessary, improve yields to dry DMF or even more critically, DMSO? (I know I'm flashing ignorance but I'm not completely alone)
I'll be happy to investigate these questions & share results as soon as I find a way to determine yields accurately.
(can Jim swim? I know it's useless but swim feels weird. Who would guess he's old school?)
One final question. If one were to make AM-2201, apparently one could substitute 1-bromopentane with 5-fluoro-1-bromo-pentyl. Is that true? Is there a way to calculate expected yield before testing? And if so, why does the currently divulged method use 5-bromopentylacetate, following additional steps thus additional cost and complication?
Hope we get somewhere.
I mean y'all and swim hhh
cheers
Here is an example of alkylation to JWH-018, 1-pentyl-3-(1-naphthoyl)indole, MW 341.4
To a 250ml 3 neck RBF fitted with thermometer, condenser and a stir bar there is added 3-(1-naphthoyl)indole (3g, 11mmol) followed by dry DMF 50ml. Potassium hydroxide flakes (1.5g, 27.5mmol 1.5eq.) were added in one portion and the setup purged with butane. The flask was heated to 60-70 degrees C on a water bath for 20 minutes with stirring. A green solution with ppt is obtained. After this time, 1-bromopentane (4.3g, 28.6mmol) was added in one portion via glass syringe. There is an immediate color change to red and the flask is heated at an internal temp of 60-65 C for 3 hours. KBr ppts in the first few minutes after addition of the alkyl halide. It is then cooled to RT and diluted with 150ml H2O, and extracted with DCM 3x 40ml. The organics are washed with water 3 times then the solvent is evaporated. There is excess bromopentane as noticed by the smell so it is removed under vacuum in a hot water bath. 3g of amber oil was obtained (8.8mmol, 80% yield) The amber oil that remains is the product. It is a pain to get it to crystallize. Only after 1 month in the refrigerator did crystals begin to form. By covering them with a small amount of IPA cleaned them up and caused all of the oil to crystallize. Once you have a seed crystal the oil can be directly crystallized after alkylation, but I have had no luck getting it to crystallize right after without the seed or with ethanol. The obtained material is completely melted by 61 C, lit Mp is 60-62 C.
The product is fucking active and is obtained as beige to yellow slightly gummy crystals. It would be best to straight chromotograph the oil but not everyone can do that.
Huffman JW, Mabon R, Wu MJ, Lu J, Hart R, Hurst DP, Reggio PH, Wiley JL, Martin BR.
“3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB(1) cannabinoid receptor”.
Bioorg Med Chem. 2003 Feb 22;11(4):539-49.
So many questions come up, I have to go over notes to include them all. I hope these issues come along as discussion progresses. One of them I have posted recently at the JWH-018 thread, which is, what is the safe(optimal) temperature to evaporate residual water, solvent and bromopentane? I have read elsewhere and on the literature DMSO being used instead, and I have tried both but crystallization was not successful so I can't determine which one is best and I can think of no way to determine this besides running a cavia sapiens operation so it's unavailable, unreliable and we are down to serious science, but rumor is that DMF is better because of the reason. And to be fair, I wasn't the one who heard this rumor. Someone I know did.
So this reaction states that dry DMF is used. Does this impact on the yield? Should KOH be dried as well? Can K2CO3 be used successfully?
Alkylations described by Billy Dampier (current hero, savior and inspiration
Thanks Billy!) use NaH as reducing agent as is widely found in the literature, and it certainly requires absolutely dry conditions unless one's intention is to destroy evidence via undocumented but widely known oxidation procedures but adb and 5cl precursor sellers have =>answered<= (I can't remember who asked, citation needed) that DMF does not necessarily need to be dried for the reaction in question, and those are corresponding alkylations, so are the sellers wrong, or is dry environment unnecessary in that case only? Would it, although unnecessary, improve yields to dry DMF or even more critically, DMSO? (I know I'm flashing ignorance but I'm not completely alone)I'll be happy to investigate these questions & share results as soon as I find a way to determine yields accurately.
(can Jim swim? I know it's useless but swim feels weird. Who would guess he's old school?)
One final question. If one were to make AM-2201, apparently one could substitute 1-bromopentane with 5-fluoro-1-bromo-pentyl. Is that true? Is there a way to calculate expected yield before testing? And if so, why does the currently divulged method use 5-bromopentylacetate, following additional steps thus additional cost and complication?
Hope we get somewhere.
I mean y'all and swim hhh
cheers