Chemistry 251 Laboratory -- Spring 2002
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Updated 4/16/02


Synthesis of Frontalin

Faculty Mentor: John Hanson

Frontalin is an anti-aggregation pheromone of the Douglas Fir Bark Beetle (a northwest pest), and is manufactured by a company in Canada ("Pherotech") for use against beetle attacks. (They actually called last year and were interested in any potential syntheses we come up with.) For more information on frontalin and its synthesis, I recommend the excellent website authored by Gerard Dupuis and Nicole Berland. One effective strategy for synthesis of frontalin involves treatment of 6-methyl-6-hepten-2-one with MCPBA followed by acid-catalyzed rearrangement of the resulting epoxide.

Scheme showing conversion of 6-methyl-6-hepten-2-one to Frontalin.

We will focus our efforts on the following strategies for synthesizing the desired 6-methyl-6-hepten-2-one.

Students Working on This Project

Lab Day Name E-mail
Monday Lindsey O'Neal
Monday Brian Birch
Wednesday Dan Wandschneider
Wednesday Nikki Alton
Thursday Aft. Amber Wade
Thursday Aft. Jason Fischer
Thursday Eve. Hattie Alexander
Thursday Eve. Kanani Dilcher

Table of Reagents and Amounts Available for this Project

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.
Reagent Source Amount/group Location Comments
p-Toluenesulfonyl chloride Aldrich
Cat. # 24,087-7
15 g TA room Water sensitive. Keep sealed.
1,4-Diazabicyclo[2.2.2]octane (DABCO) Aldrich
Cat. # D2,780-2
15 g TA room
3-methyl-3-butene-1-ol Aldrich
Cat. # 12,940-2
8 mL TA room
Cyclohexyl amine Aldrich
Cat. # 24,064-8
20 mL TA room Toxic
Acetone Aldrich
Cat. #
20 mL TA room Use high quality acetone.
3-chloroperoxybenzoic acid (MCPBA) Aldrich 5 g Organic Fridge
Methyl vinyl ketone Aldrich
Cat. # 26,954-9
10 mL Th 208 Freezer Caution: Highly Toxic. Cancer Suspect Agent. Wear gloves and work in the hood.
3-chloro-2-methylpropene Aldrich
Cat. # 28,197-2
10 mL TA room Cancer Suspect Agent. Wear gloves and dispense in the hood.
3-bromo-2-methylpropene Aldrich
Cat. # 34,583-0
2 mL TA room Cancer Suspect Agent. Wear gloves and dispense in the hood.
Zinc (granular)
20 mesh
Cat. # 4244-01
10 g TA Room
Copper(I) Iodide Aldrich
Cat. # 20,544-0
5 g TA Room Light sensitive.
Copper(I) Chloride Aldrich
Cat. # 21,294-6
5 g TA Room Moisture sensitive. Toxic.
Magnesium turnings Repackaged from Mallinckrodt 10 g TA Room
Magnesium turnings (New bottle) Fisher
Cat. #M11-500
10 g TA Room
Magnesium powder
100 mesh
Cat. # CB1196
10 g TA Room
Palladium(II) chloride Acros
Cat. # 195200050
0.2 g TA Room

Acetone Enolate (or equivalent) Alkylation

Bartlett, P.; et al. Synthesis of Frontalin, the Aggregation Pheoromone of the Southern Pine Beetle. J. Chem. Ed. 1984, 61, 816.
Perez, A.L; Gries, R.; Gries, G, Oehlschlager, A. Transformation of presumptive Precursors to Frontalin and exo-Brevicomin by Bark Beetles and the West Indian sugarcane Weevil (Coleoptera). Biorg. Med. Chem. 1996, 445-450.

One approach involves alkylation of an enolate anion (or equivalent). The Bartlett synthesis (see reference above) uses the enolate formed from ethylacetoacetate to react with the tosylate shown in Scheme 1, followed by hydrolysis and decarboxylation to afford the desired 6-methyl-6-hepten-2-one. But this has never has never worked well for us. (It didn't work well for Bartlett either, affording only a 15-30% yield.) To avoid having to do the hydrolysis and decarboxylation we could try to use an acetone enolate equivalent. A paper in Biorganic & Medicinal Chemistry (see reference above) described a synthesis of the needed 6-methyl-6-hepten-2-one using the anion formed by deprotonation of the cyclohexylimine of acetone (Scheme 1). We didn't have much luck last year, but I think it is worth looking at this reaction again.

Scheme 1. Acetone enolate alkylation strategy.

Step 1: Tosylation

Check the reports form last year. (Last year's reports are available in the Chemistry Library.) For the past few years we have used a modified procedure for the tosylation. This modified procedure uses TsCl with DABCO as a base. This eliminates the need to use pyridine (which is rather stinky). I have included information from the original article below.

This could be a much better procedure for tosylation since it avoids the use of pyridine!

Hartung, J.; Hunig, S.; Kneuer, R.; Schwarz, M.; Wenner, H. "1,4-Diazabicyclo[2.2.2]octane (DABCO) - an Efficient Reagent in the Synthesis of Alkyl Tosylates or Sufenates" Synthesis 1997, 1433-1438.

Abstract: The bicyclic tertiary amine 1,4-diazabicyclo[2.2.2]octane (DABCO) is a promising substitute not only for the widely used but hazardous and hygroscopic base pyridine in the synthesies of alkyl tosylates 3 but also for triethylamine in the preparation of alkyl sulfenates 4 from sterically hindered alcohols 2. In several provided examples the substrates 2 were completely converted into the desired products, e.g. the respective tosylates 3, which minimized subsequent separation processes. The current protocol points, in a number of cases, to nonchlorinated solvents as good alternatives to chloroform or dichloromethane and offers a workup procedure for a larger scale reaction which relies on the removal of the side products by filtration instead of the traditional extratction method using several aqueous washings.

In the general procedure they note that TsCl was recrystallized from cyclohexane.

Synthesis of O-Esters (3,4); General Procedure:
A round-bottom flask was charged with a solution of DABCO (2.24 g, 20 mmol, 10 mL of anhydrous solvent) and alcohol 2 (10 mmol) and was stoppered with a drying tube (CaCl2). The mixture was cooled to 0 C (ice bath). The respective acid chloride (in our case, tosyl chloride, 15 mmol, neat) was added in small portions over a period of 5 min which was paralleled by the formation of a precipitate. The slurry was stirred for 1h at 0 C and after removal of the ice bath until all starting alcohol 2 has been consumed [14-24 h for tosylates 3, tosylation studies using primary alcohols (not shown in Table 1) indicate that these substrates are converted to the respective tosylates within 1-3 h. It is advantageous to work up these mixtures immediately rather than allowing an extention of the reaction period to 24 h.]. The mixture was filtered and the precipitate was repeatedly washed with t-BuOME (total volume of 50 mL). The filtrate was extracted with 2 M HCl (2 x 20 mL), with 5% NaHCO3 (20 mL) and with H2O (20 mL). The organic phase was dried (MgSO4 and concentrated in vacuo. The oily to solid residues were purified by column chromatography (silica gel) using the given eluent.

Notes and Suggestions

  1. The procedure listed above talks about washing with t-butyl methyl ether, but this is probably not necessary. Try filtering the reaction mixture through a Buchner funnel, washing the solid with a small amount of dichloromethane, and then extracting the filtrate as described above.

  2. The solid that is formed in the reaction is probably DABCO hydrochloride.

  3. Because of limitations in the amount of reagents, you should not use more than 15 g of DABCO or TsCl in your procedure. Scale the literature procedure accordingly.

  4. Here is the procedure reported by Julianna Taylor and Christy Mather, two students in Spring 1998.

Step 2: Formation of Imine -- Cyclohexylamine + Acetone

Look in the lab reports from last year. The procedures were based on the one described below, but we did it on a smaller scale.

Reference: J. Org. Chem. 1972, 37, 2063.

To a mixture of 1.0 mol of cyclohexylamine and 1.1 mol of acetone were added five drops of concentrated hydrochloric acid and 7 g of 4A molecular sieve. This mixture was stirred for 30 hr at ambient temperature; KOH pellets were added and the mixture was distilled to give 92 g (97%) of the imine, bp 96-100 degrees (59 Torr).

[3,3] Sigmatropic Rearrangement

Perez, A.L; Gries, R.; Gries, G, Oehlschlager, A. Transformation of presumptive Precursors to Frontalin and exo-Brevicomin by Bark Beetles and the West Indian sugarcane Weevil (Coleoptera). Biorg. Med. Chem. 1996, 445-450.

Another strategy involves attack of the Grignard reagent formed from 2-methyl-3-chloropropene on methyl vinyl ketone producing an alcohol that undergoes a palladium catalyzed [3,3] sigmatropic rearrangement to afford the needed 6-methyl-6-hepten-2-one (Scheme 2).

Scheme 2. [3,3] Sigmatropic Rearrangement Strategy.

Formation and use of Grignard from Methallyl chloride
Notes and Suggestions

  1. Brian and Lindsey found a detailed paper on the formation of the Grignard reagent: Baker, K.V.; Brown, J.M.; Hughes, N.; Skarnulis, A.J.; Sexton, A. Mechanical Activation of Magnesium Turnings for the Preparation of Reactive Grignard Reagents. J. Org. Chem. 1991, 56, 698-703.

  2. 3/28/02 -- Nikki and Dan tried using Mg powder to make the Grignard reagent. But it didn't seem to work as evidenced by the fact that they isolated only starting materials after the reaction. (In fact we saw no evidence of Grignard formation.) We will wait and see how it goes with Hattie and Kanani tonight. We may want to try to get the Grignard forming by warming gently or by adding a small crystal of iodine.

  3. 4/3/02 -- Hattie and Kanani were also unable to get the Grignard reagent to form after stirring Mg ribbon overnight as suggested in the paper on "Mechanical Activation of Magnesium Turnings...." mentioned in Note 1 above. (It didn't look like the stirring in the round bottom flask did a very good job of producing Mg powder.) We even tried adding a small crystal of iodine without success.

  4. 4/3/02 -- Nikki and Dan found an article in Organic Syntheses (Collective Volume VI, pp 845-852) on preparing highly reactive Magnesium by reaction of MgCl2 with potassium, but it looks like it would be fairly difficult.

  5. 4/3/02 -- This week we will try preparing the Grignard reaction again, but we will try some of the following tricks for getting Grignard reagents to form:

  6. 4/4/02 -- Dan and Nikki were able to get the Grignard to form using the above tricks. After addition of a little bit of the methallyl chloride to the Mg the solution in the flask turned cloudy, and eventually a lot of precipitate was formed making the contents about the consistency of a slurpy. They filtered the mixture through a sintered glass funnel under nitrogen, and then added the methyl vinyl ketone to this solution. Their yield was not great, but it looked like the correct stuff by NMR. They will do some GC/MS to verify. We can now try to optimize this procedure.

  7. 4/4/02 -- Kanani and Hattie tried conditions similar to Dan and Nikki's but didn't see much evidence of reaction. They tried sonicating and adding a little iodododecane to get the Grignard to react. After all the methallyl chloride was added (after about 2 hours) the reaction mixture was a bit cloudy. The mixture was refluxed for about an hour at which point a precipitate, similar to Dan and Nikki's, had formed. After rereading the paper by Baker et. al. (see above) it seems that the precipitate is probably MgCl2 formed by homocoupling, thus this is an unwanted side reaction.

  8. 4/7/02 -- Dan and Nikki did a GC/MS on their product. They started at 100 degrees C for 3 minutes and then ramped to 180 degrees at 10 deg/min. They had a peak (the largest non-solvent peak) at 3.4 minutes that seems to be the desired product: weak parent at m/z 126, and a base peak at 71. Also contains M-18 and M-15 peaks as well as significant peaks at 43 and 55. We might want to try a lower temperature (80 degrees?) just so that we can see starting materials.

  9. 4/7/02 -- The NMR for 3,5-dimethyl-1,5-hexadien-3-ol was given in the Perez et. al article (see above): H-NMR (CDCl3) 1.30 (s, 3H), 1.78 (3H, s), 1.86 (1H, s), 2.30 (2H, s), 4.77 (1H, d, J=1.3 Hz), 4.92 (1H, d, J=1.3 Hz), 5.04 (1H, dd, J=10.7, 1.3), 5.23 (1H, dd, J=17.3, 1.3 Hz), 5.96 (1H, dd, J=10.7, 17.3 Hz). FT-IR (neat): 3445, 3075, 2933, 1710, 1643, 1107, 920, 777 cm-1.

  10. 4/7/02 -- The article by Perez et al. (see above) also notes that 2-methyl-1-propenyl magnesium chloride (the Grignard reagent we are trying to prepare) was "prepared by Grignard reaction between 3-chloro-2-methyl-1-propene (6.78 g, 7.4 mL, 75 mmol) and activated magnesium powder (3.40 g, 0.14 mol) in THF at 0 degrees C according to Oppolzer et al." We should order this reference: Oppolzer, W.; Kundig, E.P.; Bishop, P.M.; Perret, C. Tetrahedron Lett. 1982, 3901.

  11. 4/16/02 -- We looked at the Oppolzer reference referred to above, and the procedure they use is beyond our capabilities. (They heat the Mg in an aluminum crucible at 0.01 torr and evaporate into a rotating vessel containing THF at -110 degrees!)

  12. 4/16/02 -- I got a different, unopened, container of Mg turnings. They are much shinier than the old bottle that we were using, so I am hoping that this will help in our efforts to get the Grignard reagent to form.

  13. 4/16/02 -- Brian and Lindsey have used the new Mg and are trying the "dry-stir" method again. They flame dried their flasks and Mg under vacuum. In one flask they used a regular "octagonal" stir bar (3/4") and the Mg turnings. In the other flask we used a large (3/4") football shaped stir bar, and also added some Mg powder that we hope will help to grind up the Mg pieces. They are currently stirring under Nitrogen.

  14. 4/16/02 -- A few other ideas to try: Use the 3-bromo-2-methylpropene instead of the chloro, at least to try to start the Grignard. Use an alkyl or aryl halide that more readily forms a Grignard to help start the reaction, then switch to the chloro after some fresh Mg surface has been exposed. I was thinking of phenyl bromide. I still think that sonication might be promising.

  15. 4/16/02 -- As mentioned in a 4/7/02 note, Nikki and Dan seemed to get some product. They then did some TLC and Flash Chromatography work to purify it. Here are their notes:

  16. 4/16/02 -- The dienol that is produced in this reaction is relatively volatile (bp = 146-147 at atmospheric, and 46-47 at 10 mm) so be careful not to over rotovap.

Zn-Cu Couple or Organocuprate

Trehan, I.R.; Singh, J.; Arora, A.K.; Kaur, J.; Kad, G.L. Synthesis of undecan-3-one; (+/-) frontalin; (+/-)-endo-, and (+/-)-exo-brevicomin under sonochemical aqueous conditions. Indian J. Chem. 1995, 396-398.

The Zn-Cu couple mediated coupling of methallyl bromide and methyl vinyl ketone is reported to produce the desired 6-methyl-6-hepten-2-one in 80% yield. Alternatively, it might be possible to use the cuprate formed from the Grignard reagent produced from 3-bromo- or 3-chloro-2-methylpropene to do a conjugate addition into methyl vinyl ketone.

Scheme 3. Zn-Cu Couple or Organocuprate Strategy

Zinc-Copper couple procedure from Indian J. Chem. article.

To the zinc-copper couple prepared as above, was added 3-buten-2-one (1.0 mmole, 0.070 g) and 1-bromo-2-methylpropene [This must be named incorrectly, the structure in the paper is that of 3-bromo-2-methylpropene.] (1.5 mmol, 0.203 g) and the mixture was sonicated for 45 min. It was quenched with saturated brine and worked-up as usual to furnish pure 6-methyl-6-hepten-2-one after chromatography over silica gel and eluting with pet. ether: ethyl acetate (9:1) (0.114 g, 80%). NMR and IR data provided.

Notes and Suggestions

  1. 3/27/02 -- Brian and Lindsey tried the Zn-Cu couple procedure, but didn't isolate any of the desired product. The Zn definitely turned black after sonicating for a few minutes with the CuI, but it may be that the Zinc that we are using (20 mesh) is not fine enough, or maybe the reaction is slower than we expected. They will try it again, but follow the reaction by GC/MS. If that doesn't work, we'll order some new Zn powder.

  2. 4/4/02 -- Still no luck. But The Wizard has some Zn powder, so they'll try that next time.

  3. 4/15/02 -- Brian and Lindsey tried three times and never saw any product. They've decided to abandon this approach and will try working on the Grignard strategy.