Index

• Faculty Mentor: John Hanson (hanson@pugetsound.edu)
• Project TA: Kim Dill-McFarland (kdillmcfarland@pugetsound.edu)
• Students working on this project
• 4-Isobutylacetophenone Synthesis
• Table of Reagents
• Conversion of Carbonyl to Methylene
• Step X: Superbase Carboxylation

Introduction

Ibuprofen is the active ingredient in a number of over the counter pain relievers, e.g. Advil, Motrin, and Nuprin. It is one of the top-ten drugs sold worldwide, and, although it has been shown that only the S enantiomer has the desired biological activity, it is currently sold as the racemate.

Synthesis of Ibuprofen from 4-Isobutylacetophenone

For the past few years we have synthesized Ibuprofen using an interesting sulfur ylide strategy, but since we have worked out most of the bugs in that synthesis it is time for a new challenge. In our previous synthesis we used 4-isobutylacetophenone (1) as our starting material, and since we still have a 50 g bottle of that available, I would like to use that as our starting material. Some students who worked on the Ibuprofen project in 2002, found a procedure using a "superbase" that allowed them to deprotonate 4-isobutylethylbenzene (2) and react the resulting anion with CO₂ to make Ibuprofen (see reference above). So your job is to find an efficient method to convert 4-isobutylacetophenone (1) to 4-isobutylethylbenzene (2). If we complete the synthesis of Ibuprofen, I'd like to look at methods for resolving it to produce the active enantiomer.

The table below lists the chemicals that we will have available for this project. If you need something that is not on this list, consult with the mentor for your project. Also note the "Amount/group" column. This is the total amount of material available for each group to use on the project.

Step 1-X: Reduction of Carbonyl to Methylene

References

1. Zaccheria, F.; Ravasio, N.; Ercoli, M.; Allegrini, P. "Heterogenous Cu-catalysts for the reductive oxygenation of aromatic ketones without additives" Tetrahedron Lett., 2005, 46, 7743-7745.

   (2/28/10) Chris Shaw tracked down this reference. The catalyst requires some preparation, but might be doable. But probably more importantly for us, the article reviews other methods (complete with citations) for accomplishing this transformation. Let's take a look at these.

2. Lau, C.K.; Dufresne, C.; Belanger, P.C.; Pietre, S.; Scheigetz, J. "Reductive Deoxygenation of Aryl Aldehydes and Ketones and Benzylic, Allylic, and Tertiary Alcohols by ZnI₂-NaCNBH₃" J. Org. Chem. 1986, 51, 3038-3043.
3. Bulavka, V.N. "Reduction of alkylarylketones to alkylbenzenes with zinc dust and hydrochloric acid: comparison with zinc amalgam reductions" 8th International Electronic Conference on Synthetic Organic Chemistry. ECSOC-8, November 2004. http://www.usc.es/congresos/ecsoc/8/GOS/025/index.htm.

Notes and Suggestions

1. I've done some preliminary searching and there are a lot of potential avenues to accomplishing this transformation. However, many of them use expensive or hazardous reagents or conditions. When you do your SciFinder search don't confine yourselves to this exact transformation, but look for any method that works for acetophenone derivatives. It might also be fruitful to look in more general organic references (like the advanced organic texts we talked about in lab). Also, don't think that you need to do this in one step. For example, one approach might be to reduce with NaBH₄, convert to the bromide with HBr, and then remove the Br with nickel boride. But it seems like we should be able to find something easier.


2. (2/28/10) You might want to look in the older literature. Some of the newer methods are cool, but often require specialized equipment/reagents. Try looking in some of the advanced texts we discussed a couple weeks ago in lab.


3. (2/28/10) Another useful approach might be to search for ways to remove benzylic alcohols. I'm sure we can readily reduce the ketone to an alcohol using NaBH₄. It seems like H₂/Pd should work.


4. (3/26/10) Copper Catalyst Method. Chris and Juliet started the prep of the copper catalyst (see the Zaccheria, et al. citation above). They did the reaction on half the scale listed in the paper. They dissolved 4 g of Cu(NO₃)₂ in 25 mL water and then added concentrated NH₄OH until the pH was 9. (They used one of the pH probes set up for use in Chem 230 for acid/base titrations.) As I recall, they said this took about 9 mL of NH₄OH. They then added 10 g of our regular flash silica gel and let the dark blue mixture stir for 20 minutes. They then placed the mixture in an ice bath and added about 600 mL of water to the stirred solution over the course of about an hour to try and get the copper to precipitate, but nothing happened. Eventually they added about 20 drops of concentrated H₂SO₄, at which point they got a precipitate to form. The solution became colorless and the silica gel was now a dark blue. They then collected the silica gel by filtration through a Buchner funnel, washed it with water, and then placed it in a beaker. This was then placed in an oven at 120 degrees C over the weekend.


5. (3/29/10) Molly and Andrea established the following GC/MS method (ibuprofen1): 100 degrees C for 2 min, then 10 degrees C/min up to 250 degrees. The starting isobutylacetophenone has a retention time of approximately 8.3 minutes. They are doing the ZnI₂/NaCNBH₃ method (see the Lau et al. citation above) at RT. No reaction apparent after about 1.5 hours, they will check tomorrow.


6. (3/30/10) ZnI₂/NaCNBH₃ Method. Molly and Andrea found that after stirring overnight at room temperature they had 1/3 starting material and 2/3 alcohol! There was only about 0.5% of the alcohol. They are going to heat it to reflux.


7. (3/30/10) Zn dust/HCl Method. Nina and Anna are trying the Zn dust/HCl method. After refluxing for a couple hours they analyzed by GC/MS and found that they had 92% starting material, 6% product, and 0.7% of the alcohol. After another few hours they were up to 15% product.


8. (3/30/10) GC/MS Conditions. We are using a method called "ibuprofen1" that starts at 100 degrees C for 2 min, then 10 deg/min to 250 degrees. Here are the retention times and characteristic ms fragments.
   


9. (3/30/10) ZnI₂/NaCNBH₃ Method. Desiree, Julianna, and Roger analyzed their reaction after one hour at reflux. They found 24% starting material, 65% alcohol, and 10% product! They will let it reflux overnight.


10. (3/30/10) Another possible method. When I was at the ACS meeting last week I saw a poster from some students at Pacific University describing a convenient method for reduction of alkenes and alkynes that I think might also work for the reduction of acetophenones. I'd be interested to have someone try this method. They used 1 mmol of the alkene or alkyne in 5 mL of either water, isopropanol, or toluene and combined with 4 equiv of NaBH₄, 2 equiv of AcOH, and 1-5 mol% Pd/C. The reaction was typically complete in 30 min at RT, although I expect it might be slower in our case.


11. (3/31/10) Zn dust/HCl Method. After refluxing overnight, Nina and Anna found that the product was about 90% of the mixture, with another 8% or the mixture corresponding to the the alkene shown below. The mixture also contained about 1% of starting material and 1% of an isomer of the product. The crude NMR after workup is a bit messy, some purification will be needed, but this method looks very promising. I don't yet know the yield.
    
12. (3/31/10) ZnI₂/NaCNBH₃ Method. Cassie and Justin analyzed their reaction (by GC/MS) after refluxing for 18 hours. The mixture contained 95% of the desired product 5% of the alcohol and no starting material! I haven't heard about their crude yield or what the NMR looked like.


13. (3/31/10) Copper Catalyst Method. The blue, copper-impregnated silica gel, was heated at 350 degrees for 4-5 hours and turned green.


14. (4/2/10) ZnI₂/NaCNBH₃ Method. Jessie and Auriel used about 0.5 g of the starting acetophenone, and refluxed for 28 hours. GC/MS showed that they had about 94% product and 6% of the alcohol. They filtered through celite and rotary evaporated the filtrate to yield about 0.6 g of crude product. They will analyze by NMR when the NMR is back up.


15. (4/2/10) Copper Catalyst Method. The green pre-catalyst was heated with a heating mantle containing sand in a flask under hydrogen from a balloon to approximately 240 degreees. After the temperature exceeded 200 degrees the green solid turned black over a couple minutes, indicating reduction to the desired catalyst. After sitting under hydrogen for about 10-15 minutes, the catalyst was pumped on a high vacuum pump for about 15 minutes. Approximately 0.5 g of starting isobutyrylacetophenone was dissolved in 8 mL toluene with the catalyst and heated to 90 degrees under a hydrogen atmosphere. GC/MS after about 5 hours showed mainly starting material. We will let it go over the weekend and see if anything happens.
16. (4/6/10) Copper Catalytst Method. After stirring at 90 degrees under hydrogen over the weekend, the reaction was still primarily starting material. It is unclear why we are not getting any reaction, but Chris and Juliet are going to switch to the Zinc dust method. They will try a variation of adding ethanol as a cosolvent.
17. (4/6/10) Zinc Dust/HCl method. Here is the procedure used by Nina and Anna:
    • 1. Add zinc dust (2.56g, 0.0392 mol) slowly to 4-isobutylacetophenone (1.05 mL, 5.7 mmol).
      2. Add water (2.8 mL) and concentrated HCl (2.8 mL, 0.0336 mol).
      3. Heat the reaction to reflux and monitor regularly with GC/MS. Every hour or so add concentrated HCl (0.3 mL).
      -For GC/MS: Before adding 0.3 mL HCl each hour,
      -Remove a couple drops from the reaction
      -Dilute with 1 mL CH2Cl2
      -Wash with 1 x 1 mL sat. NaHCO3 and 1 x 1 mL H20
      -Dry with Na2SO4
      -Pipet into GC/MS vial
      4. When the reaction is complete, cool the solution, extract with ethyl ether, and dry with Na2SO4.
      5. Filter and evaporate. Then analyze crude product with NMR.
18. (4/6/10) Granular Zinc Method. Nina and Anna set up a reaction under the same conditions as before, but substituted "Granular Zinc" (20 mesh). The reaction went even faster than before! After 1.5 hour they only had 20% starting material left, and after 2 hours the starting material was gone! They had about 95% desired product and about 2.5% of isobutylstyrene plus a little bit of an isomer of the desired product. They are going to add hexane for their workup.... Stay tuned.
19. (4/6/10) Zinc Dust Method. Molly and Andrea are following the standard Zinc Dust method, but starting with 2.5 g of isobutylacetophenone. Their reaction is also proceeding nicely.
20. (4/7/10) Sodium Borohydride & Pd/C Method. Desiree, Juliana, and Roger are doing the sodium borohydride and Pd/C method. After stirring for several hours at room temperature, the GC/MS indicated about 5% starting material, 90% alcohol, and 5% product. They let it stir overnight, but not much had changed so they added more sodium borohydride, acetic acid, and Pd/C and are heating it to see if anything further will happen.
21. (4/7/10) Granular Zinc in EtOH/conc. HCl. Chris and Juliet used granular zinc and conc. HCl, but substituted ethanol for the water used in the original procedure. After refluxing for 2 hours the reaction was complete as judged by GC/MS. They added hexane and water and did an aqueous workup. I am looking forward to seeing their yield and NMR.
22. (4/7/10) Desiree, Juliana, and Roger finished worked up their reaction from their original ZnI₂/NaCNBH₃ procedure. The NMR (see below) looks good.
    



23. (4/12/10) Nina and Anna only got about 0.3 g of product and the NMR was not clean, so they are going to repeat the reaction. Molly and Andrea's flask broke, so they weren't able to isolate any product, so they are also going to repeat the procedure.
24. (4/12/10) Here is a workup procedure:
    • After the reaction is complete, remove the flask from the heat and let it cool to room temperature.
    • Add 10-20 mL of hexane to the reaction flask and swirl to get the product to dissolve.
    • Decant or filter (to remove the Zn) into your separatory funnel. (You can wash with a little hexane to help the transfer.)
    • Remove the lower aqueous layer and then place the hexane layer into a flask.
    • Put the aqueous layer back into the separatory funnel and extract with about 5-10 mL of additional hexane.
    • Remove the lower aqueous layer and then add the first hexane extract back in with the one remaining in the sep. funnel.
    • Wash the combined hexane layers 1 x 20 mL saturated sodium bicarbonate and 1 x 20 mL saturated sodium chloride.
    • Dry the hexane layer with sodium sulphate or magnesium sulphate.
    • Filter and rotovap to give a colorless oil. Get the yield (be sure to tare the flask) and an NMR.
25. (4/14/10) Granular Zinc in EtOH/conc. HCl. Chris and Juliet obtained about 1.2 g of crude product after aqueous workup. (They started with 1.05 mL of the ketone.) By NMR the crude product looked to be a mixture of SM (30%) and Product (70%) with some other minor impurities. They will be looking at methods for purifying this.
26. (4/14/10) Granular Zinc Method. Desiree, Roger, and Juliana set up a reaction with 5 g of starting ketone. After refluxing for an hour or two, they had about 30% product and 70% starting material, so they let it reflux overnight. One of the possible reasons for this going slower is that the reactants doesn't fully dissolve in the water, and if it is not stirred vigorously the zinc sits in the bottom and the organic layer is on the top. I think it would be useful to look at the ethanol method in more detail.
27. I really hope we can get some material purified this week, either by distillation or flash chromatography. Let me know what your yields and crude NMR's are looking like.
28. (4/15/10) Granular Zinc Method. Jessie and Auriel started with 3 mL of starting ketone and 7.68 g Zinc, 8.4 mL HCl, 8.4 mL water. Refluxed for 1 hour and 40 minutes and was complete by GC/MS. They let it sit overnight and used hexane workup, washed with sat. NaCl, dried Na2SO4, filtered and rotovapped to give about 1.8 g of oil. After sitting for several days there was a solid present. They ran a pseudo flash column with 10 g of silica gel and eluted with 50 mL of hexane, rotovapped to give 1 g of a colorless oil. H-NMR looked good. (Although the carbon seemed have some extra peaks.) They will use this for the superbase reaction next week.
29. (4/15/10) Granular Zinc in EtOH/conc. HCl. Chris ran their product through a short flash column and eluted with hexane (similar to what Jessie and Auriel did above). (TLC in hexane actually shows several peaks?) They ended up getting what looks like a reasonable mass recovery, although we don't have an exact amount yet. H-NMR an C-NMR looks great. The impurity that was there before seems to be gone. Chris's carbon NMR is shown below:
    
    

Step X: Superbase Carboxylation

1. See notes from 2002.
2. Here is a procedure adapted from the Schlosser paper (above).

   Do the following reaction in a flame-dried flask under nitrogen. Heat a well-stirred solution of 1 g (6.2 mmol) of p-ethylisobutylbenzene, 12 mmol of 1.6 M butyllithium in hexane, and 12 mmol of potassium t-butoxide to 60 degrees for several hours. Then pour onto crushed dry ice covered with 30 mL of THF. Evaporate the solvents and dissolve the residue in water (30 mL). Wash the aqueous phase with diethyl ether (3 x 10 mL). (Since the solution will be basic at this point, your ibuprofen will be deprotonated and thus will NOT go into the ether phase.) Acidify the aqueous layer to < pH 1 and extract with diethyl ether (2 x 10 mL). Dry the combined ether extracts (with sodium sulphate or magnesium sulfphate) then filter and evaporate the ether to give the crude product.

3. (4/21/10) Juliana, Desiree, and Roger tried this reaction last night starting with 1 g of p-ethylisobutylbenzene. The reaction was very darkly colored. They heated for approximately 1.5 hour and then poored onto dry ice/THF. After workup they obtained about 120 mg of an oil. NMR looked like mostly starting material. I'm worried that the extraction procedure might not be doing a good job of pulling out the ibuprofen. Maybe we should try using dichloromethane.
4. (4/21/10) Nina and Anna also tried the reaction yesterday, but I haven't heard about their results.