Does this sound remotely familiar? Your new kick-ass synthesis plan requires a highly functionalized benzene, let’s say with 4 or 5 different substituents in defined positions as the key starting material. As you search for it, you find one or two semi-suspicious vendors who say they can deliver it to you in “6-12 weeks”, which is as we all know a euphemism for “this compound never existed, but we’ll sure try our best!”

So, you start considering making the material yourself instead, only to realize that it adds 8-14 steps to your otherwise ingenious scheme.

Let’s say the key starting material in question (more of less arbitrarily chosen – no literature search conducted on my behalf) is 4-bromo-6-butyl-3-chloro-2-methoxybenzoic acid (1).

Compound 1

So, how to best make 1? The first thing I guess anybody does is some sort of a retrosynthetic analysis (whether it happens on paper or in your head), by looking for obvious disconnections. For instance, we have a carboxylic acid ortho to a methoxy; perhaps some sort of DOM followed by quenching with dry ice would work? That bromine sure sits in problematic position, meta to the methoxy, para to the carboxylic acid, that spells trouble. And so on.

Good and bad disconnections

Here’s were today’s tip comes in. Stop disconnecting the substituents (red scissors)! Cut the ring apart instead (green scissors)!

Having worked with thiophenes a lot, one could argue that I’m a tad biased, which is true of course, but still I can assure you that preparing thiophene 2 would be a walk in the park compared to making benzene 1 by conventional transformations.

Compound 2

So, how does thiophene 2 help us here? Here comes the cool part. Thiophenes are easily oxidized to their S,S-dioxides, which turns them into powerful diene substrates for DA type chemistry. Now, if you treat thiophene S,S-dioxide 3 with 1-trimethylsilylhex-1-yne (slight chance it doesn’t even have to be TMS protected for this specific example to work) under DA conditions this neat little cascade is going to happen. First a [4+2] cycloaddition, and as you heat it more, the formed intermediate will expel sulfur dioxide in a retro-[4+1] fashion, and release your desired product just like that. (TMS groups usually just fall off spontaneously, especially in the microwave. If not, feed the crude material with TBAF.)

Pretty neat, huh?

cascade cycloadditions

Disclaimer 1: The above example was chosen as a pedagogical illustration, I didn’t turn to the literature this time around, so don’t expect this exact example to work out of the box.

Disclaimer 2: You would probably get a the other regioisomer too in the cycloaddition steps, but an even better design will overcome that too. (Endo/exo ratio does not matter as the final product is flat.)

I do think this highlights a couple of important concepts: Think outside the box when you disconnect and plan ahead. If you need to make a benzene, you don’t necessarily have to start with a benzene. There are so many cool ring forming reactions available to us today. This is one of the more useful ones, one that has helped me several times in very different projects. Add it to your mental list and at least consider something along these lines if you ever need a highly functionalized aromatic.

Finally, this strategy is by no means restricted to benzenes. It has been used to make anthracenes, naphtalenes, pyridines and many other heterocylces. I’m sure you can find a number of useful literature references in SciFinder or Reaxys if you only know what to look for – which you now do. Good luck! (Also, preparing demanding benzenes in as few steps as possible is a popular orgo exam question. Hint to all students: I’m sure any professor would give you extra credits if you propose something like this. Big chance the creator of the exam didn’t consider these possibilites himself.)

 

3 Responses to Powerful method for highly functionalized aromatics

  1. drfreddy says:

    Due to popular demand, a couple of literature references:

    JACS 1988, 110, 6598-6600. (DOI: 10.1021/ja00227a069)

    JACS 1990, 112, 5654-5655. (DOI: 10.1021/ja00170a048)

    JACS 1994, 116, 10275-10283. (DOI: 10.1021/ja00101a051)

    Tetrahedron Lett. 1994, 35, 2709-2712. (DOI: 10.1016/S0040-4039(00)77012-2)

    JOC 1998, 63, 4912-4924. (DOI: 10.1021/jo971710z)

  2. milkman says:

    I wonder how much the oxidised sulfur would effect the HOMO of the diene in this example (in real life)? With heat and the locked s-cis diene I think you’d get away with it with most 2pi systems…

    Here is a sweet analogous example using a sulfolene as a masked diene, the sulfolene collapses under heating to form the diene, this kind of chemistry has been done on quite impressive scale by the corresponding author in another paper.

    http://www.sciencedirect.com/science/article/pii/S0040403900799680

  3. Karl Collins says:

    I really like this Dr Freddy, cheers. Doing terpene total synthesis I don’t really get much time to look into interesting ways of making traditional ‘medchem’ type motifs; it is just the standard taught chemistry that usually springs to mind. This is a really nice disconnection – hopefully it will go to the PERMANENTLY STORED section of my brain.

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