Design and synthesis of a variety of 3 alkylanilines
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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 63701. Overview.

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Design and synthesis of a variety of 3 alkylanilines

Design and Synthesis of a Variety of 3-Alkylanilines:

Multiple and Varied Synthetic Approaches for Intermediates for Potential Antibacterial Compounds.

Mark McGill* andBruce A. Hathaway

Southeast Missouri State University

Cape Girardeau, MO 63701


Overview

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.


Synthetic outline

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.


Nitration reduction scheme

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.


Nitration reduction results

Nitration-Reduction Results

  • Difficulty maintaining cold temperature with nitration.

  • Nitration yields need to be improved.

  • Wolff-Kishner reduces both ketones and nitro groups.


Nitration reduction discussion

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.


Nitration of benzophenone

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: 2.74 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.


Friedel crafts acylation experiment

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.



Wittig catalytic reduction results

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.


Wittig procedure discussion

Wittig Procedure Discussion

In a round bottom flask, 0.200 moles of 1-bromohexane, 250 mL p-Cymene, and 0.200 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 0.0753 moles solid NaOH, 20 mL 1,4 dioxane (w/0.5 mL H2O), and 0.020 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.


Sonogashira alkyne coupling reduction to 3 alkylanilines

Sonogashira Alkyne Coupling:Reduction to 3-Alkylanilines

This experiment was repeated for 1-hexyne, 1-heptyne, 1-octyne, 1-decyne, and 1-dodecyne.


Coupling reaction results

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.


Reduction results

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.


Sonogashira scheme discussion

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.


Conclusion

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.


Further work

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.


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