Chemistry 251 Laboratory -- Spring 2001
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Last updated on 2/16/01

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Synthesis of Frontalin
Faculty Mentor: John Hanson

Bartlett, P.; et al. J. Chem. Ed. 1984, 61, 816.
Perez, A.L; Gries, R.; Gries, G, Oehlschlager, A. Biorg. Med. Chem. 1996, 445-450.

Frontalin is an aggregation pheromone of the Southern Pine Beetle. It possesses an interesting tricyclic structure containing an acetal linkage. The Bartlett synthesis (shown below) is a five step process with the ring construction occurring in the last step by an acid catalyzed reaction on an acyclic precursor. Unfortunately, the second step in which a tosylate is displaced by an anion formed from ethyl acetoacetate does not work well. We need a new approach. A recent paper described an alternate synthesis of the 6-methyl-6-hepten-2-one using the cyclohexylimine of acetone. We will prepare this imine and try this reaction.



Students Working on This Project
Lab Day Name E-mail
Monday
Monday
Tuesday Drue Pickens dpickens@ups.edu
Tuesday Dan Thorner dthorner@ups.edu
Wednesday Noelle Conforti lconforti@ups.edu
Wednesday Nichole Ashworth nashworth@ups.edu
Thursday Aft. Andy Nelson acnelson@uswest.net
Thursday Aft. Jeff Locke jlocke@ups.edu
Thursday Eve. Alison May amay@ups.edu
Thursday Eve. Kristi Knopke kknopke@ups.edu


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
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 Fridge

Step 1: Tosylation

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



Try scaling down this procedure and see if it works.

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).