Strained Systems Make a Comeback!

Bunker, K. D.; Sach, N. W.; Huang, Q.; Richardson, P.F. Scalable Synthesis of 1-Bicyclo[1.1.1]pentylamine via a Hydrohydrazination Reaction Org. Lett. ASAP August 11th, 2011

Have you ever noticed that projects generally work better when you are under pressure? Well, maybe this isn’t true for all people but I have recently found this to be true for myself. With the departure of our undergrads last week and the beginning of classes (and teaching) in only two weeks, I have found myself putting in much longer days than usual in order to get through my to do lists and (hopefully) get another publication out before the end of the month. Currently, my focus has been on wrapping up (and in some cases re-doing) a project I assigned to two of our undergrads. The project was a great success in terms of the chemistry, but in order to be publishable, some work needed to be done by the pros 😛 (me and my lab-mate, Mike). I’m currently halfway through writing the manuscript and so far it’s looking very pretty promising. I’m going to aim for Org. Lett. as the target journal for this work. Once that’s finally done, and we wrap up another, more process chemistry related project (again by the end of the month), I will get back (finally) to working on our collaborative work with Dr. Tilley. And after that, who knows? I am excited though for the upcoming semester. Not only will I likely be TAing for an organic chemistry course, I will also be assisting Mike in designing an advanced organic chemistry course to be given in the spring of next year. Mike and I hope to impart on the students the basic skills needed by every organic chemist in a research lab (e.g. flash column chromatography, vacuum distillation, designing a synthesis of a target compound from a more practical perspective than those seen in organic texts, and performing advanced reactions which you will no doubt need to do during your graduate career such as a cross coupling or Weinreb ketone synthesis). Additionally, many of our undergrads who were with us this summer will be returning this fall so I am excited to work with them again as well. I can’t wait for the end of the month and hopefully soon I can share with you all what I’ve been up to! And now…on to some awesome chemistry!
I’ve certainly been on a Organic Letters kick lately. This latest article comes from a rather surprising source considering the content of the article: the La Jolla Laboratories of Pfizer Worldwide R&D. What immediately attracted me to this article, despite it being somewhat of a targeted synthesis, was the starting material depicted in the graphical abstract. [1.1.1] Propellanes are not your run-of-the-mill sython and considering the fond place I have in my heart for strained systems, I couldn’t pass this one up.

The article begins by outlining that one of the up and coming strategies for medicinal chemistry is gaining “access to novel chemical space”. One area that is somewhat underdeveloped in this regard is small molecules with rather unusual structures, such as bicyclopentanes (and in my opinion, bicyclobutanes). In particular, Bunker and his colleagues at Pfizer were interest in bicyclo[1.1.1]pentylamine. Why you might ask? Well, many recent medicinally-active structures feature the bicyclo[1.1.1]pentylamine moiety. The article gives two examples, one being a new quinolone-based antibiotic and the other is a heat-shock protein inhibitor.

Bicyclo[1.1.1]pentylamine is a known, but fairly challenging molecule to synthesize (especially on a large scale). A well-known and quite remarkable chemist, Dr. Kenneth Wiberg (whom I consider the king of strained systems) was the first to prepare it back in the beginning of the 70s.

Starting from a compound also first prepared by his lab, Wiberg took bicyclo[1.1.1]pentane and performed the arduous task of derivitizing it (which proved surprisingly more difficult than one would expect). However, he ultimately found that bicyclo[1.1.1]pentane was prone to free-radical reactions and by treating this bicyclic system with oxalyl chloride while being irradiated with ultraviolet light, the acid chloride derivative could be obtained. Subsequent hydrolysis with water followed by treatment with sodium azide in acidic conditions (Schmidt Conditions) gave the bicyclic amine, albeit in low overall yield. Moreover, it involved reactions that are unamendable for scale-up (e.g. the Schmidt reaction involves the formation of hydrazoic acid, a highly toxic and potentially explosive material).

More recently, Toops and co-workers have attempted synthesis of this bicyclic amine via organostannanes. Again this method also involves toxic materials and low overall yields which cannot be used to produce the large quantities need by Pfizer. Seeking the most practical way to synthesize bicyclo[1.1.1]pentylamine, Bunker and co-workers decided to start with the strained [1.1.1] Propellane and carry it to the iodo azide like the Timberlake group did. This iodo azide is attractive since all you need to do is remove the iodide and reduce the azide to an amine.

While Timberlake was unable to do reduce his iodo azide, Bunker and his group managed to do this by using hydrogen gas and Pd(OH)2 on carbon under acidic conditions. However, just like many of the groups before them, they obtained unacceptably low yield. Upon doing some digging, Bunker determined that just like bicyclo[1.1.1]pentane, [1.1.1] propellanes are prone to free-radical functionalization. With this information in hand, they decided to take some chemistry developed Carreira and co-workers involving transition-metal mediated free radical hydrohydrazination (say that five times fast!).

Starting from [1.1.1] propellane yet again, which was be prepared via a modification of the Wiberg method from the dibromocyclopropane, Bunker and co-workers performed a hydrohydrazination using tris(dipivaloylmethanto)manganese and DBAD. This gave the Boc- protected hydrazine which was de-protected simply using HCl to give the hydrazine salt. Hydrogenation using PtO2 in methanol yielded the HCl salt of bicyclo[1.1.1]pentylamine in 62% overall yield! Moreover the authors were able to scale up the reaction to yield 100 grams of bicyclo[1.1.1]pentylamine! And the best is yet to come according to the last line of the article so I await more from Pfizer regarding other strained systems. I thoroughly enjoyed this article and hope you do to! Ckellz…Signing off…



  1. Nice article – I was almost tempted to write something about this myself! I once used HN3 while my boss was on holiday, he was pretty angry when he came back and realised what I’d done – apparently our department has seriously restricted its use. I’d love to know the mechanism of that hydrohydrazination – I guess it’s like the Mukaiyama ‘hydration’ in Baran’s cortistatin synthesis (replace DBAD with O2), but I’m still not sure how either work. Incidentally, your Carreira link is broken (although the paper is still easy to find). And you probably mean amenable, rather than amendable.

    • Thanks! Yeah I really wouldn’t want to touch HN3 with a ten foot pole. It seems like really nasty stuff, but then again so are a lot of things that organic chemists work with on a regular basis (t-butyl lithium, NaCN, Dess-Martin etc.). I’m not all that surprised that your department has restricted use on the stuff. It has the best (or worst) of both worlds: toxicity and explosive nature. And as for the hydrohydrazination, I think you are indeed right, it’s very similar to the Mukaiyama hydration reaction. My guess is that the manganese (in the case of this article, Cobalt in the case of Mukaiyama) stabilizes the diradical state of DBAD (or O2). This will then add to an olefin (or an olefin-like bond such as the [1.1.1] Propellane bridgehead bond) giving a carbon radical which can be reduced by PhSiH3. This will also form a heteroatom bound to the organometallic complex being utilized. The silyl radical can either continue the reaction (promoting more radical formation) or react with the metal-coordinated species to give a silane bound to a heteroatom which cleaves upon workup. Or at least that’s my best guess and my mechanism seems to corroborate with the one proposed originally by Mukaiyama . And thanks for the catches, I got them all fixed up!

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