Retron of the Week: 1,3-Dipolar Cycloaddition

Happy football season everybody! Go Steelers!

Five-membered heterocyclic rings are often best assembled via 1,3-dipolar cycloaddition methods. Although regio- and stereoselectivity for these reactions can be difficult to predict from first principles, they do usually exhibit a high degree of selectivity. The basic idea of any 1,3-DC reaction is the combination of a three-atom, dipolar pi system with a two-atom pi system (the “dipolarophile”). Dipolarophiles are typically alkenes or alkynes, but the versatility of the dipolar component is what really makes this class of reactions useful synthetically. They’re so reactive that usually, unactivated alkenes react just fine with a little heat. Check out all the nifty heterocycles you can make using a 1,3 dipole and ethylene!The figure above is missing one class of dipoles that has become important recently: carbonyl ylides. These can be made by the Rh2(OAc)2-assisted reaction of a carbonyl group with a diazo compound, with the negative charge ending up on the carbon formerly attached to the diazo group. Di- and tetrahydrofurans can be made using these dipoles, depending on whether the dipolarophile is an alkyne or alkene, respectively.

There’s no use employing this reaction retrosynthetically without some way to make the odd-looking dipoles, so a number of methods have popped up for synthesizing these interesting characters from nitro compounds, imines, oximes, and the like. Primary nitro compounds can be dehydrated to form nitile oxides, the upper right of the figure. Hydroxylamines can also condense with aldehydes to form nitrones (second from the bottom), with dehydration as the driving force once again. In a particularly neat preparation, azomethine ylides (bottom) can be generated in situ by thermal opening of a substituted aziridine. Azides can be made using sodium azide and secondary or primary halides. Just setting up substrates for 1,3-DC reactions has, as you can see, led to quite a bit of interesting chemistry.

Coming soon: the intriguing story (or lack thereof…you have been warned) of 1,2-cyclobutadiene.

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2 Comments

  1. wait, isn’t that the classic Click reaction?

    What role does the Rh catalyst play in that carbonyl ylides? How the fudge do you pronounce a ylide?

    Reply

  2. Sure enough, the addition of an azide to an alkyne is the original Click reaction.

    Reaction with the Rh catalyst leads to a carbene-esque intermediate where the diazo group used to be; attack from a lone pair on the carbonyl oxygen then leads to the ylide. A lot of reactions involving rhodium(II) acetate and the diazo group are known; in every case, the carbon attached to the diazo group behaves like a carbene at some point. Cyclopropanation of alkenes, C-H insertion, and carbenoid cycloadditions can all be catalyzed using diazo compounds and rhodium(II) acetate.

    I pronounce it “ill-id.”

    Reply

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