It’s Just Another Mannich Monday…

Belanger, G.; O’Brien, G.; Larouche-Gauthier, R. Rapid Assembly of Quinolizidines via Consecutive Nucleophilic Cyclizations onto Activated Amides Org. Lett. ASAP July 14th, 2011

After another long week and a half in the lab, its nice to return to blogging! The Leadbeater lab has been incredibly busy these past couple of days. On Monday we received a planned visit from Dr. Tilley and his students to discuss the progress of our work in a joint group meeting. It proved quite productive and has possibly lead to new avenues for us to explore down the line (and have further collaborations). Meanwhile back at the lab, we have made much progress not only in terms of our collaboration but in terms of renovating our lab. We recently acquired (thanks to myself and Mike Mercadante, my lab-mate and close friend) a new vacuum pump. Not only is it in good condition (it is slightly used), it pulls an excellent vacuum (0.05 mmHg!). There is nothing like a good pump to make your life easier (especially when stripping off those pesky high boiling solvents like DMF or performing vacuum distillations on particularly heavy substrates). Our work with Dr. Fenteany, which feels like a long time ago now, should be submitted soon (very excited!). Also, the link to my new article is up. It was a relatively quick project but showed how microwaves can significantly shorten reaction times (in this case for disulfide formation)by allowing one to reach extreme high temperatures. In other news, our undergrads are really doing quite well. One of them just completed a short synthesis of a substrate for a project that we are currently working on (and in good yield!) while the other has solved the problems we have been having with another project Mike and I developed. The latter is well on her way to completing the project by the end of the summer (or at least getting close to it) while the other (a UConn student) will be staying on into next semester! So in terms of chemistry, I really have nothing to complain about besides the norm (reaction not working or having a difficult purification). So without further adieu, on with the review!
So this week’s article comes from, surprise surprise, Organic Letters, a journal consistently gives me good articles not only to review but just to read for pleasure. What really grabbed me about this article is the complexity of the structures being created. Not only is it a relatively simple reaction to do (or so it appears) but it yields a quad center and a tertiary nitrogen-fused bicycle (known as a quinolizidine).
These sorts of structures are often nestled into the larger framework of various alkaloid.

According to the article, there are a relatively limited number of ways to make these sorts of compounds and most are somewhat entailed or lengthy. Even few examples exist of performing a dual cyclization to form both rings in one shot. Most methods make one ring with some sort of functionality in it to allow for a second ring closure later. Existing dual or “one-pot” preparations include RCMs, Michael additions, Pictet-Spengler like condensations, cycloadditions or reductive amininations. Seeking to expand the tool box, Belanger and co-workers sought to apply their existing monocyclization parameters (for the formation of nitrogen-containing bicycles) to performing a dual cyclization (starting from acyclic materials). They believed that they could first induce a Vilsmeier-Haack-like reaction to give monocyclization and follow it up with a intramolecular manic…I mean Mannich :P. In my opinion, it’s not a true Mannich per say. I would argue it’s more analogous to the Pictet-Spengler reaction (a modified Mannich).

Initially the authors were worried that such a cyclization would be difficult and possibly disfavored. They assumed monocyclization would be facile. However, this would remove the more reactive internal nucleophile (olefin) with the more active electrophile (iminium ion). The second iminium ion could easily tautomerized to an enamine (and is already less electrophilic and the first imine) and the remaining nucleophile (the other olefin) is likely to be the less reactive of the two. Both these factors could have destroyed their chance at a second cyclization. But, thankfully, their fears were abated when they observed dual cyclization on their symmetrical test substrate. They did not however that two isomeric products were obtained but the ratio could be tweaked by altering the sterics of the system (i.e. making it a acetamide etc.).

Not all of their substrates behaved as planned. One of the biggest issues they ran into is competitive aromatization (at elevated temperatures) to a pyridinium ion. The authors attribute this to steric hindrance in some of their substrates with significantly slows the second cyclization. As a way to overcome this limitation and to gain better control over the reaction, they decided to attempt to utilize a “latent” nucleophile for the second cyclization. They hypothesized that the second cyclization could be promoted by the “unmasking” of this latent nucleophile (aka enhancing its reactivity to improve the chance of the second “Mannich-like” step).

To test this, the authors relied on some old chemistry developed by the Overman group. In their case the “masked” nucleophile would be an alkyne, a normally unreactive substrate to cyclizations of this type. Moreover, instead of using a allylsilyl “nucleophile” they used the substantially more reactive silylenol ether. However, this was very strategic. While the enol ether is more reactive to monocyclization, it inhibits a second cyclization by iminium deactivation via “electrodonation”. The second cyclization could be promoted by the addition of a bromide salt in acetonitrile while spontaneously converting the enol ether to its corresponding ketone. Not only does this provide enhance control, by leads to a halide containing product which could be further functionalized.

Overall, I would say this is one of the more impressive (and detailed) articles that I’ve seen. While nitrogen chemistry isn’t my normal cup of tea, I really enjoyed reading this article so go check it out! Congratulations to Belanger and co-workers on a job well done! Ckellz…Signing off…



  1. sorry for nitpicking – in the last scheme you have the silyl enolether C=C on a bridgehead carbon (very unfavorable) from the fourth structure onwards, the C=C should be with the other alpha carbon instead.

    • Good spotting, yeah I knew there was something odd when I was drawing but I couldn’t place my finger on it, I will correct that shortly!!!

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