Design%20and%20Synthesis%20of%20a%20Variety%20of%203-Alkylanilines:

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 63701

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.

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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 23 nitric acidsulfuric 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.

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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.

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.

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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.

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Sonogashira Alkyne CouplingReduction to
3-Alkylanilines

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

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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 119 Ethyl AcetateHexane 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 119 Ethyl AcetateHexane 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 119 Ethyl AcetateHexane 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.