Synthesis Challenge

Question

I have been trying to make a monomer reached a dead end in the middle. A B C are the products I have made so far respective order. After reaching C I wanted to prepare 2 but could not find a way to do so. haloform had a high chance of brominating Hydroxyl group at other end I speculate. Acid catalysed Haloform on A did not result in 1 but ended up with B again [with suprisingly 2 % more yield than I got with simple base hydrolysis. Now at this point I have no option but to produce 1 and then go for 2. I need references or suggestion to make 2 from C cause that will greatly reduce my work load. I am running short of time for my summer project.

Answer 1

The route I would try to prepare 1 would be to purchase 4-Bromo-4'-hydroxybiphenyl which is commercially available (Alfa Aesar sells it - see http://www.alfa.com/en/catalog/A10819)

First Step: 1) Protect phenol moeity with benzyl group via refluxing a solution of 4-Bromo-4'-hydroxybiphenyl (1.0 eq, 1.00 g), milled potassium carbonate (4.0 eq), benzyl bromide (1.1-1.25 eq), and acetone (25-30 mL). Reaction will most likely take 10-20 hours to be complete. Once reaction is complete, cool to ambient temperature and filter reaction mixture. Concentrate the filtrate to dryness.

• If you dont have Benzyl bromide, you can use benzyl chloride (1.1-1.25 eq) and potassium iodide (0.1-0.5 eq).

**Alternatively, instead of filtering the reaction mixture, you could add water (50-75 mL) to the mixture to cause the product to crystallize out (this will only work if the product is a solid at room temperature). If you dont see any solids after adding water, you can try adding an ice-water bath under the mixture to encourage crystallization.

Once isolated the material, allow the protected product (benzyl ether) to be dried in a desiccator or vacuum oven to remove traces of water.

Second Step: 2) Perform a Grignard reaction with protected product (above). The Grignard reaction can be prepared either in THF or diethyl ether using Mg metal/iodine as catalyst, or using isopropylmagnesium chloride solution in THF).

Once the Grignard reaction has been prepared, pour the reaction onto dry ice. This will form the Protected Compound 1 as the magnesium salt. Add water to solubilize the salt, then wash the mixture with diethyl ether (1-2 times to remove impurities) and then add concentrated $\ce{HCl}$ (37%) until pH 1-2 is acheived which will precipitate out the protected Compound 1.

Third Step: 3) Dissolve protected Compound 1 in ethyl acetate, add small amount of Palladium on carbon, and hydrogenate the mixture under hydrogen pressure (balloon pressure will work just fine too) at room temperature overnight.

Once reaction is complete, degas the mixture with nitrogen or argon, filter, and concentrate to provide the desired Compound 1.

Answer 2

If you have the capability, convert the ketone to an enol ether and ozonolyse / oxidative cleave the alkene portion. You might want to cleave your acetate first, make your ether and then silylate , but you'd be silylating to make the enol ether anyway.