Construction of Fused Heterocyclic Architectures by Formal [4+1]/[3+2] Cycloaddition Cascade of Sulfur Ylides and Nitroolefins

Construction of Fused Heterocyclic Architectures by Formal
[4+1]/[3+2] Cycloaddition Cascade of Sulfur Ylides and Nitroolefins

Liang-Qiu Lu, Fang Li, Jing An, Ji-Ji Zhang, Xiao-Lei An, Qiu-Lin Hua, and Wen-Jing Xiao

DOI: http://dx.doi.org/10.1002/anie.200904766

It’s methodology time as can be seen from the title. A short paper featuring a nice cascade reaction for the construction of these highly functionalized heterocycles (don’t know the trivial name, if there is one, for these kind of structures; the names generated from ChemDraw are… useless….)

Overview:

overview_121109

A formal [4 + 1] addition of the ylide is followed by an intramolecular [3 + 2] cycloaddition of the formed nitronate to give this odd looking heterocycle.

After some efforts to improve the yield, CHCl3 was identified to be the best solvent. During the studies 10 derivatives were made including different substitution patterns on the phenyl moiety, a thiophenol, a naphthalene and one acyclic derivative (referring to the starting ether).

Also 12 derivatives were made varying the residue on the ylide. The yields are generally above 75%, in some cases up to 99% (!).

Additionally the d.r. is really high (in all cases 95 : 5 minimum) with respect to the one diastereomer represented above.

So what’s the mechanism? It might look like this:

Mechanism:

mechanism_121109

The ylide attacks the nitro group via Michael addition followed by a SN2 displacement of dimethylsulfide. The formed nitronate then acts as a 1,3-dipole and reacts in a cycloaddition with the olefin of the α-β-unsatured ester to give the product.

It can easily be seen that after formation of the first stereocenter the following four are formed stereospecifically.

The products of this reaction sequence can be hydrogenated in the presence of Raney Ni to give fused pyrroline rings:

Reduction:

functionalization_121109

And at long last it was tried to improve the ee by adding a symmetric urea in half stoichiometric quantities (which leaves room for some improvements) but does the job very well:

Stereoinduction:

stereoselectivity_121109

I think my shortest piece to date… Maybe when they discover a suitable natural product owing this kind of framework then this methodology could show its full potential.

Nice work!

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2 Responses

  1. I couldn’t agree with you more..

  2. Admirable read!

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