Cross Coupling of Anilines

A fascinating paper appeared on the JACS ASAP site this morning from Ueno, Chatani and Kakiuchi. They used a ruthenium catalyst to carry out a cross coupling of an aryl amine with a phenyl boronate. What is remarkable is the fact that the transition metal did oxidative addition to an aryl-nitrogen bond. Success of the reaction was dependent on having a chelating carbonyl group adjacent to the amine, however, this is still the first example of oxidative addition to a hitherto unreactive C-N bond.

Satoshi Ueno, Naoto Chatani, and Fumitoshi Kakiuchi, DOI: 10.1021/ja0713431

ASAP Thursday

Some good papers have shown up on ASAP this week. Here's two that rose to the top for me.

First is a contribution from Shu Kobayashi with some very interesting chemistry using chiral Calcium complexes. The reaction he investigated was the Michael addition of glycine derivatives with acrylates. He showed the importance of an enolizable proton on the bis-oxazoline ligand and suggests that the reactive species is a calcium Brønsted base. This generates a chiral calcium enolate that undergoes Michael addition to the acceptor. Subsequently, an intramolecular Mannich reaction ensues to afford pyrrolidines in very high selectivity.

Susumu Saito, Tetsu Tsubogo, and Shu Kobayahsi, JACS, DOI: 10.1021/ja0709730

Organocatalysis is all the rage now, and even we are trying our hand at some. Xiao has just reported a slightly new twist on organocatalysis by carrying out an intramolecular Friedel-Crafts reaction with indoles to form tricyclic compounds. Selectivities are are pretty good in some cases.

Chang-Feng Li, Hiu Liu, Jie Liao, Yi-Ju Cao, Xiao-Peng Liu, and Wen-Jing Xiao, OL, DOI: 10.1021/ol0703130

Beta Amino Acid Rearrangement

Here's the answer to the mechanism question I posed at the end of the last post. Some have suggested a 4-membered ring intermediate. While that cannot be ruled out, a mechanism that does not include the high strain of a bridged 4-membered ring seems more plausible.

Since this is an aminoacid, it will exist in it's zwitterionic form. Thus, the quaternary ammonium will not be acylated. The carboxylate is converted to a mixed anhydride. Then it undergoes a beta-elimination of the ammonium to open the 6-membered ring. This is followed by an acylation of the resulting amine to form the rearranged lactam.

This reaction was reported by Henry Rapoport (JACS 1970, 92, 5781). He cites an older paper by Ferles (Coll. Czech. Chem. Commun., 1964, 29, 2323.

Update: As liquidcarbon points out in the comments, the free amine of the ring-opened intermediate above would likely be acetylated in refluxing acetic anhydride. Another possible route to the product would involve an intramolecular acylation forming a bridging 4-membered ring, followed by beta elimination. Possible, but I'm not sure how well the bridgehead hydrogen sigma orbital would overlap with the sigma star orbital of the C-N bond.

Mechanism Challenge Answered

Tynchtyk, over at Chemist in a Transition State, posted a very interesting transformation and challenged us to propose a mechanism. Here is the reaction.

At first glance, this looks like some kind of reductive amination reaction. However, on closer inspection, you can see that there is one less carbon in the product than the starting material. Furthermore, there are no reducing agents present, only acid (and presumably water). Of course the obvious starting point is to react the secondary amine with the aldehyde to form a cyclic imminium structure. Once generated, this is nicely set up to undergo a [3,3]-sigmatropic rearrangement to transfer an allyl group to the imminium carbon. The resulting formaldehyde imminium product is then hydrolyzed in the presence of water to afford the product plus an equivalent of formaldehyde. The full mechanism is shown below. Notice I am a stickler for showing every proton transfer step! No shortcuts here.

Tynchtyk says this problem appeared in a science olypiad for High School Students in Moscow. I wish our high school education here in the states was up to this kind of challenge.

Thanks, Tynchtyk, nice problem! In the spirit of problem solving, let me pose a new challenge. This is one of my favorite transformations.

Feline Frolics

I have two cats and they drive me absolutely nuts. Always demanding and always getting in trouble. Today was no different. I had need of some thyme for my spice cupboard, so I snuck out at lunch and stopped by my favorite health food store that has a huge array of dried herbs and spices in bulk. I bought an ounce of thyme and some other goodies and stopped off at home to put them away. No sooner did I drop the bag on the kitchen floor and head to the 'little chemists room' did my biggest pain in the ass, Sam, discover a new toy. Yes, a small little plastic bag of thyme. By the time I got back to the kitchen, he had ripped the bag open and was squirming around on the floor in a big mess of herbs! *sigh* You'd think it was catnip or something, the way he was carrying on. Out of curiosity, I dug up information on the compound found in catnip. It turns out to be nepetalactone. Nothing I could find indicated that thyme contains this terpene. So what was Sam all worked up about? Well, the major volatile constituent of thyme is the terpene thymol. Very different structure than nepetalactone. Although thyme does not contain nepetalactone, catnip does contain significant amounds of thymol. Interestingly, thymol is also used as in ingredient to repel feral cats. Sam sure is odd.

ASAP Thursday

The first thing I do when I get into the lab in the morning is make my coffee. The second thing is to see what has appeared on the web journals. I suppose since I'm blogging that I should share with you the articles that catch my eye. Here's a couple from today.

Karl Scheidt has a very nice example of umpolung chemistry catalyzed by N-heterocyclic carbenes in a [3+3] cycloaddition. This appeared on the web yesterday.

Audrey Chan and Karl A. Scheidt, JACS DOI: 10.1021/ja0709167


Interestingly, I was just teaching my synthesis students about the utility of diazo compounds for cyclopropanation and Wolff rearrangements and what appears on OL this morning? A very nice and practical method for the preparation of diazo compounds. This could come in handy.

Muhammad I. Javed and Matthias Brewer, OL DOI: 10.1021/ol070515w

YACB - Yet Another Chem Blog

I need to do a blog like I need another hole in my head. Does the world really need another chemistry blog? Probably not. So, why am I doing this? I have no idea. I guess because it's fun? There's so much science out there that seems very impersonal. Perhaps blogging about chemistry allows us to inject our personal views and commentary on current chemistry. My hope is that this blog allows me to present what I find interesting in the world of Organic Chemistry and hopefully inspires people to pursue this wonderful scientific discipline.