1. Design and Synthesis of a Variety of 3-Alkylanilines:
Multiple and Varied Synthetic Approaches for Intermediates for Potential Antibacterial Compounds.
Mark McGill* and Bruce A. Hathaway
Southeast Missouri State University
Cape Girardeau, MO

2. Overview
3-alkylanilines are required for the synthesis of 3-alkylphenyltriazines, a class of potential antibacterial compounds. Though there are many potential routes to 3-alkylanilines, one must consider the nature and position of the substituents on the benzene ring in order to select a suitable and logical pathway to the desired product. For example, the difficulty of placing an alkyl group (or useful transformational group) on a deactivated nitrobenzene ring.

3. Synthetic Outline
Considering this aspect of synthetic planning, three different approaches to the 3-alkylaniline synthesis were chosen for investigation. These include: the Wolff Kishner reduction of nitrated alkyl phenyl ketones, catalytic hydrogenation of Wittig derived alkenes, and catalytic hydrogenation of Sonogashira alkyne coupling reactions.

4. Nitration-Reduction Scheme
Three trials were attempted for the nitration of alkyl phenyl ketones with subsequent Wolff Kishner reduction of the Trial 1 product. The Trial 3 product currently awaits reduction.

5. Nitration-Reduction Results
Difficulty maintaining cold temperature with nitration.
Nitration yields need to be improved.
Wolff-Kishner reduces both ketones and nitro groups.

6. Nitration-Reduction Discussion
Multiple procedures are available for nitration reactions. Generally, one can cool ~15 mL of concentrated sulfuric acid in an ice bath and add alkyl phenyl ketone with stirring. Add nitrating mixture (cold 2:3 nitric acid:sulfuric acid) dropwise, but keep the temperature below 0° - then stir 10 minutes more. Pour over cracked ice and water with stirring. Work-up varies from washing to extraction with ether. The Wolff-Kishner reduction simply involves refluxing alkyl 3-nitrophenyl ketones with hydrazine hydrate and HO- in diethylene glycol. Overall yields could be improved with nitration optimization.

7. Nitration of Benzophenone
A procedure similar to previously discussed nitration gave yield to a mixture of products. A 24 hour reflux in ethanol left some undissolved solid. Hot filtration gave yield to two different solids: grams of what appears by NMR to be relatively pure di-nitrated benzophenone as well as 5.24 grams of an impure mixture of nitrated (and di-nitrated) benzophenone. Nitration worked, but not selectively.

8. Friedel-Crafts Acylation Experiment
The Friedel-Crafts Acylation reaction was utilized to generate product that would reduce to yield an aniline with an sp3 carbon bonded to a benzene ring. This could be modified to yield a 3-alkylaniline.

9. Wittig – Catalytic Reduction Scheme

10. Wittig-Catalytic Reduction Results
Viable route to 3-alkylanilines.
Reduction product difficult to purify.
Alternative procedures and modifications could be applied to help increase yield.

11. Wittig Procedure Discussion
In a round bottom flask, moles of 1-bromohexane, 250 mL p-Cymene, and moles triphenylphosphine were refluxed 3 hours. Next, 8.57 grams (0.020 mol) of solid product from this reflux were added to a mixture of moles solid NaOH, 20 mL 1,4 dioxane (w/0.5 mL H2O), and moles of 3-nitrobenzaldehyde to reflux for 4 hours. The dark solution was filtered and the filtrate rotary evaporated. This oil was washed with pentane, filtered and evaporated again. The oil was purified by a crude silica column using CH2Cl2 as eluent. Both alkene isomers were reduced catalytically using a Parr Shaker.

12. Sonogashira Alkyne Coupling: Reduction to 3-Alkylanilines
This experiment was repeated for 1-hexyne, 1-heptyne, 1-octyne, 1-decyne, and 1-dodecyne.

13. Coupling Reaction Results
Incredibly difficult to purify (both alkyne and reduction).
Reductions are not guaranteed or clear cut.
Does provide 2-step method to 3-alkylanilines.

14. Reduction Results
NMR confirms the successful reduction to form 3-octylaniline, 3-dodecylaniline, and 3-hexylaniline with relative purity. NMR indicates that the reductions of 1-(3-nitrophenyl)-hept-1-yne and 1-(3-nitrophenyl)-dec-1-yne were only partially complete when the reaction ended.

15. Sonogashira Scheme Discussion
This path has proven successful for generating moderate yields of reasonably pure 3-alkylanilines. Purification of the alkyne products was attempted by column chromatography using 1:19 Ethyl Acetate:Hexane as eluent. Perhaps a more effective method would be to initiate the column using hexane as the eluent. Then, one could gradually increase polarity with ethyl acetate – which would allow for greater control of the separation. Also, the reductions that should have produced 3-heptylaniline and 3-decylaniline ceased prematurely. This can be remedied by running the reduction reactions again.

16. Conclusion
This path has proven successful for generating moderate yields of reasonably pure 3-alkylanilines. Purification of the alkyne products was attempted by column chromatography using 1:19 Ethyl Acetate:Hexane as eluent. Perhaps a more effective method would be to initiate the column using hexane as the eluent. Then, one could gradually increase polarity with ethyl acetate – which would allow for greater control of the separation. Also, the reductions that should have produced 3-heptylaniline and 3-decylaniline ceased prematurely. This can be remedied by running the reduction reactions again.

17. Further Work
This path has proven successful for generating moderate yields of reasonably pure 3-alkylanilines. Purification of the alkyne products was attempted by column chromatography using 1:19 Ethyl Acetate:Hexane as eluent. Perhaps a more effective method would be to initiate the column using hexane as the eluent. Then, one could gradually increase polarity with ethyl acetate – which would allow for greater control of the separation. Also, the reductions that should have produced 3-heptylaniline and 3-decylaniline ceased prematurely. This can be remedied by running the reduction reactions again.