Comments on: Neglected lab solvents

By: Matthias Goehl (@enzy84)

Matthias Goehl (@enzy84) — Fri, 12 Aug 2011 19:55:23 +0000

We use MTBE as a common substite for diethylether for in extractions an recrystallisations. Most times its even superior in regards to solubilty, recrystallisation (higher bioling point/temp range) etc.
Although toxic, chloroform and MeOH (most times mixtures have synergetic effects) are are sometime solvents of chioce for really polar stuff like some alkaloids, amino acid derivates and so on. You can even filtrate an crude amino acid over plain silica by eluating with Chloroform/MeoH/aqueous ammonia 80:35:4 (or similar). I´ve done that in a enzymatic kinetic resolution to remove enzym junk (enzym and substrate was required at a 1:1 or more mass ratio) before doing RP-18-chromatography. DCM doesnt substitute nice in this case.

By: Northwest AJ

Northwest AJ — Tue, 21 Jun 2011 07:38:25 +0000

I can’t say I know any appropriate employers, but as a postbac science student, I spent long nights reading your entertaining anecdotes in this and other blogs. You’d make a damned awesome teacher: your descriptions of chemical reactions leap to life, rather, in more ways than one. Best wishes to you.

By: tuky tuky

tuky tuky — Mon, 13 Jun 2011 21:57:38 +0000

cheers mate! I think I will tosylate the pyrrole N first, that seems to help too. Then play with anhydrous conditions…

By: milkshake

milkshake — Sun, 12 Jun 2011 23:30:43 +0000

Electrophiles like chloropyridines, and chloropyrimidines do get activated by protonation, sometimes it actually helps to add a drop of methanesulfonic acid to the reaction – this works even in the presence of amine excess. I don’t have any reference but you can take my word for it – I did it quite a few times. You can use 2-propanol too but in many cases the reaction temperature is above bp of 2-propanol so you would need a pressure flask. So I was looking for some higher-boiling secondary alcohol and I ended up using 1-methoxy-2-propanol because we had a bottle of it (its cheap), the bp is reasonable so you could pull it off on rotavap. Other higher alcohols are typically not miscible with water so you can’t precipitate the product by drowning the reaction mix in water, and primary alcohols are too nucleophilic, they have a solvolytic liability with halopyridines.

By: Baltic

Baltic — Sun, 12 Jun 2011 12:30:41 +0000

About 1-methoxy-2-propanol being useful for SNAr of halogenated heteroaromatics with amines – is there a literature refference for this?

By: milkshake

milkshake — Sun, 12 Jun 2011 05:15:15 +0000

You should look up publications from group of Dr. Michal Hocek in Prague, they have been doing lots of medicinal chemistry on purines there at the Institute of organic chemistry and biochemistry, and I remember that they were publishing on purine Suzuki couplings. I think he also co-wrote some review on purine chemistry few years back. Maybe you should send him an e-mail – I bet he would be delighted that you contacted him.

http://www.uochb.cz/web/structure/303.html?do%5BloadData%5D=1&itemKey=en_1

From my limited experience with somewhat similar heteroaromatic substrates, I think that you do have a problem with competing protolysis of ArPdX (the produced Pd(II) probably gets recycled back to Pd(0) by oxidative homocoupling of 2 equivs of boronic acid).
You should test few different diphosphines – sometimes it helps to modify the catalyst, I have seen examples where the unwanted reductive dehalogenation in Suzuki was limited by a careful ligand choice. One good catalyst to try is PdCl2(dppf). But I would also try the anhydrous conditions with Cs2CO3 powder in THF or dioxane, with simple Pd(PPh3)4, and with added activated 4A molecular sieves. I have actually done anhydrous Suzuki once before (on a pyrone substrate that was falling apart in water) and it worked well but it was somewhat slower than usual aqueous Suzuki so it needed higher reaction temperature). The other thing you can do is to trasform your boronic acid by KHF2 to K[ArBF3] salt, that ones are supposedly very nice for anhydrous Suzuki. Another possibility is to use Stille coupluing with ArSnBu3.

A procedure for anhydrous Suzuki is here: http://orgprepdaily.wordpress.com/2006/11/28/2-thianthren-1-yl-6-morpholin-4-yl-pyran-4-one-a-suzuki-from-hell/
By the way, in this original procedure I would replace the microwave heating with conventional heating on oil bath, in a pressure vial – dioxane heats up with great difficulty in microwave (it absorbs microwaves poorly because because it has no dipole).

By: tuky tuky

tuky tuky — Sat, 11 Jun 2011 12:42:06 +0000

Dear milkshake,
I’m running a Suzuki coupling on a chloro-iodo-purine-like substrate and I’m only recovering protodehalogenation product and protodehalogenation + suzuki at the chloro position product. Any tips on how to get this iodine to react and avoid this problem? I am avoiding alcohols as solvents but there’s 2M aq carbonate in the mixture, plus rx is always properly degassed.
Cheers!

By: milkshake

milkshake — Thu, 09 Jun 2011 10:14:00 +0000

For Buchwald arylation I would try peroxide-free THF with cesium carbonate solid and Pd2(dba)3 with Xanphos (1:1 Pd-diphosphine ligand) at reflux. If there is no reaction I would heat it in a pressure flask to 100C. The other catalyst to try would be simple Pd(PPh3)4. These two catalyst worked reasonably well with 4-chloropyridines for me. (Buchwald type of hindered biaryl phosphines may not be suitable for strongly coordinating substrates such as these)

By: madForIt

madForIt — Thu, 09 Jun 2011 09:56:49 +0000

Thanks both of you guys,
i’ll try Acetone-K2CO3 for sure. I am starting from Chloroquinoline and hydrolizing the Chloro to Hydroxy because of the poor reactivity as an electrophile. The other way should be Buchwald arylation between phenol and chloroquinoline, but i have to find out the right cat-ligand couple.
Thank you again.
cheers

By: milkshake

milkshake — Thu, 09 Jun 2011 05:20:41 +0000

Can you access the 4-chloroquinoline and react it with a nitrophenol?

The only trick I know, how to alkylate O preferentialy over N in hydroxypyridines, is to use very hard electrophiles, for example oxonium salts, alkyl triflates, and also Mitsunobu reaction with alcohols. But this will not help you since there is no obvious way of modifying the arylation in this way (by replacing fluoronitrobenzene with a harder electrophile). So I don’t know