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
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
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
O
O
HNO3, H2SO4
R
R
Cold (Corson & Hazen)
R = any alkyl chain
+
O
O
R
2
+
+
O
-
N
O
5 NH2NH2
KOH
Diethylene Glycol
reflux
-
N
O
R
2
+
6 H2O
5 N2
NH2
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
Trial
1
2
3
Trial
1
2
Nitration of Alkyl Phenyl Ketones
Product
Weight Melting Point
3-nitroacetophenone
3.44 g
61 °C - 66 °C
3-nitropropiophenone
--N/A
3-nitropropiophenone
NMR
Confirms
No
Confirms
Wolff Kishner Reduction of 3-Nitroacetophenone
Product
Weight Melting Point
NMR
3-ethylaniline
6.968 g
liquid
Confirms
3-ethylaniline
6.071 g
liquid
Confirms
% Yield
20.86%
N/A
% Yield
117.62%
82.41%
Difficulty maintaining cold temperature with nitration.
Nitration yields need to be improved.
Wolff-Kishner reduces both ketones and nitro groups.
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
O
O
HNO3, H2SO4 (Cold)
* Adams, Johnson, Wilcox
+
O
-
N
O
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
O
O
Cl
O
Benzene
+
N
O
Trial
1
AlCl3, 
O
+
N
O
Friedel-Crafts Acylation Experiment
Product
Weight Melting Point
NMR
4-nitrobenzophenone
2.568
Confirms
% Yield
22.29%
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 Scheme
P(C6H5)3
R
Br
p-Cymene (* Delmas)
Br
R
-
P(C 6H5)3
R - any alkyl group
Br
R
-
P(C 6H5)3
NaOH, 1,4-dioxane
R
3-nitrobenzaldehyde
+
O
-
N
O
R
Ethanol, 5% Pd/C
R
+
+
O
-
N
O
4 H2
+ 2 H2O
in Parr Shaker
NH2
Wittig-Catalytic Reduction Results
Wittig - Catalytic Reduction by Reaction Step
Step
Product
Weight Melting Point
NMR
1 hexyltriphenylphosphonium bromide 66.15 g
180 °C
Confirms
2
1-(3-nitrophenyl)-hept-1-ene
1.404 g
N/A
Confirms
3
3-heptylaniline (impure)
0.934 g
N/A
Confirms
% Yield
77.32%
24.29%
76.24%
Viable route to 3-alkylanilines.
Reduction product difficult to purify.
Alternative procedures and modifications could be applied
to help increase yield.
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
R
Br
+
Alkyne
Stir under Nitrogen
24 Hrs.
+
O
-
CuI, (Ph3P)2PdCl2,
Et2NH, (Room °C)
N
O
+
O
O
-
N
O
5 H2
+
N
O
Pd (cat.)
H2N
R
R
This experiment was repeated for 1-hexyne, 1-heptyne,
1-octyne, 1-decyne, and 1-dodecyne.
Coupling Reaction Results
Sonogashira Coupling of Alkynes with 1-bromo-3-nitrobenzene
Melting
Alkyne
Product
Weight
NMR
Point
1-octyne
1-(3-nitrophenyl)-oct-1-yne
0.875 g
N/A
Confirms
1-dodecyne 1-(3-nitrophenyl)-dodec-1-yne 1.961 g
N/A
Confirms
1-hexyne
1-(3-nitrophenyl)-hex-1-yne
2.779 g
N/A
Confirms
1-heptyne
1-(3-nitrophenyl)-hept-1-yne
3.40 g
N/A
Confirms
1-decyne
1-(3-nitrophenyl)-dec-1-yne
4.29 g
N/A
Confirms
% Yield
48.61%
42.72%
86.04%
impure
impure
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 of Sonogashira Coupled Alkynes
Melting
Reduction Product Weight
NMR
Point
3-octylaniline
0.786 g
N/A
Confirms
3-dodecylaniline
0.727 g
N/A
Confirms
3-hexylaniline
2.779 g
N/A
Confirms
3-heptylaniline
3.40 g
N/A
No
3-decylaniline
4.29 g
N/A
No
% Yield
94.74%
40.84%
85.07%
impure
impure
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
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
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
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.