Diels Alder Class 2 March 8, 2011 Last time we talked a lot about highly reactive dienes, especially those developed by the group of Sam Danishefsky. ne more example of an interesting diene is isobenzofuran: Isobenzofuran by itself is not stable enough to be isolated, but various analogues of it are isolable. Isobenzofuran acts as a diene with the two bonds of the furan (five membered ring) with typical dienophiles: Always remember that you form one more six membered ring in your product than what you started with. What is interesting about isobenzofuran is that it undergoes a retro Diels Alder reaction very easily to lose the oxygen and generate two aromatic rings. Retro Diels Alder reaction just means a reaction in which a ring falls apart through the movement of six electrons simultaneously. So the net result of this type of reaction is that you have replaced a furan ring with an additional aromatic ring. ther dienes also undergo retro Diels Alder reactions. Researchers have used this reaction to synthesize polycyclic aromatic hydrocarbons (PAHs) in general, as you add benzene rings in a linear fashion, the resulting compounds become less and less stable: Pentacene cannot be synthesized by itself, but you can add enough functional groups to stabilize it and synthesize it. ne example of how people can synthesize pentacene is from the Diels Alder reaction of an isobenzofuran (diene) and anthraquinone (dienophile). The retrosynthesis is shown below:
R 1 R 1 + X The way this actually worked in the forward direction is shown below: K that will end our discussion of specific dienes, and we will move on to a discussion of dienophiles. First I will go through several common dienophiles and their nomenclature: Most of these (except for acrylonitrile) have two electron withdrawing groups attached to the double bond, which enables these compounds to be highly reactive dienophiles. DMAD has a triple bond, which reacts exactly the same way as the double bonds do in the Diels Alder reaction, however you end up with an additional double bond in your six membered ring product: Cycloalkenones are in general not good dienophiles, because they only have one electron withdrawing group and no other driving force for reactivity:
(1) Cyclobutenone ne new dienophile (developed just in 2010) was cyclobutenone: This cyclobutenone reacts very quickly with a variety of dienes, especially compared to the larger ring analogues. The enhanced reactivity is probably due to ring strain making the double bond more reactive. Here is an example of a few Diels Alder reactions with cyclobutenone: The real advantage to these products is that they can easily undergo a variety of ring expansion reactions: And the reason that nobody thought about using cyclobutenone as a dienophile before 2010 is that it is not so easy to synthesize. The synthetic route to cyclobutenone is shown below:
(2) ther reactive dienophiles: Several other highly reactive dienophiles are part of hetero diels alder reactions. So far we have mostly talked about diels alder reactions involving six carbon atoms. However, you can replace one or more of those atoms with a heteroatom (nitrogen, oxygen, etc) to generate heterocycle compounds. These are called hetero Diels Alder reactions. The oxo Diels Alder reaction involves a carbonyl compound (where the oxygen itself is one of the six reacting atoms): The aza Diels Alder reaction involves a nitrogen atom in one or both of the reaction partners: The imine that is needed for the aza Diels Alder reaction is often generated in situ (during the reaction) from the reaction of an amine with formaldehyde: via the in situ generated imine: Several common dienophiles used in hetero diels alder reactions are shown below:
Imines Diazo compounds: Here s an interesting example that combines something from the last test with new material: In this reaction they use an N heterocyclic carbene to generate an activated enolate / Breslow intermediate from the alpha beta unsaturated aldehyde. This double bond then acts as a dienophile in a hetero Diels Alder reaction. The enolate form is the one that reacts in the Diels Alder reaction. This again adds another interesting option for retrosynthesis. If you look at the lactone product, you could think about making it via an esterification reaction, or via Grubbs at the double bond, but now you can also retrosynthesize it with a hetero Diels Alder reaction.