Organic Chemistry

2022
November 21, Pereira

Synthesis of substituted N-phenylmaleimides and use

in a Diels–Alder reaction: a green multi-step
synthesis for an undergraduate organic chemistry
laboratory
Areleen Fernanda Castro Suarez
Miguel Ángel Carvajal Guapacha

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QUÍMICA INDUSTRIAL – TECNOLOGÍA QUÍMICA

FACULTAD DE TECNOLOGÍA
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Presentation summary R G Á N IC A

1. Introduction
2. Problem statement
3. General and specific objective
4. Materials and methods
5. Results and analysis
6. Conclusions
7. Recommendations and perspectives
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1. Introduction R G Á N IC A 1

• N-phenylmaleimides
Cyclic imides
Biological activities:
-Antifungal
-Antitumor
-Antibacterial
Anti-nociceptive

• Maleimide-excellent dienophyl moiety

• Maleimides synthesized as potential acetylcholinesterase acetylcholinesterase inhibitors.
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2. Problem statement R G Á N IC A 2

• "art of organic synthesis".

• Green chemistry
• Atomic economy
• Waste reduction
• Synthesis design
• Efficiency
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3. General objective R G Á N IC A 3

Efficiently synthesize N-phenylmaleimide precursors for a

Diels-Alder reaction for a second-year organic chemistry
course.
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3. Specific objectives R G Á N IC A 4

1- Identify and understand various Green Chemistry

principles associated with a green reaction such as atom
economy, use of safer chemicals, waste reduction, design
for energy efficiency, and inherently safer chemistry for
accident prevention.

2- Enable students to use NMR spectroscopy data to

identify the synthesized Diels–Alder product.
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4. Materials and methods R G Á N IC A 5

• FTIR spectrometer.
• Characterized by 1H and 13C NMR.
• Deuterated dimethyl sulfoxide (d6-DMSO).
• Deuterated chloroform (CDCl3).
• TMS.
• TLC
• DigiMelt MPA-160.
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4. Materials and methods R G Á N IC A 6

Synthesis of N-(chloro)maleanilic acid (3)

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4. Material and methods R G Á N IC A 7

Synthesis of N-(4- Synthesis of N-(4-

chlorophenyl)maleimide chlorophenyl)maleimide (4) with
(4) with thermal heating microwave heating

Microondas Anton Paar Monowave

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4. Materials and methods R G Á N IC A 8

Diels-Alder reaction
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5. Results and analysis R G Á N IC A 9

Amine acylation
Solvent-free synthesis
Background information
Experimental data
%yield Reaction time (min)
% yield Reaction time (min)
Trujillo-Ferrara et al. 96-99 120
Students 66 10
Saedi 92 30
Table 2. Results obtained by students.
Table 1. Results from previous studies.

Alternative synthesis
Experimental data
% yield Reaction time (min)
Alternative synthesis #1 62 5
Alternative synthesis #2 87 5

Table 3. Results obtained by students

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5. Results and analysis R G Á N IC A 10

Synthesis of maleimide

Background information
Experimental data
Kumar et al
% yield atomic efficiency (%)
%yield Reaction time (min) atomic efficiency (%)
Investigation 70
method #1 67 8 48 51
Students 55
method #2 71 8 27
Table 4. solvent-free methods Table 5. Results with the traditional method

Background information
atomic efficiency (%)
Reddy et al.
92%
Le et al.
Table 6. Results obtained in two additional reports
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5. Results and analysis R G Á N IC A 11

Diels-Alder reaction with Diels-Alder reaction with microwave

thermal heating heating
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5. Results and analysis R G Á N IC A 12

Implementation with other anilines and dienes

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6. Conclusions R G Á N IC A 13

• A three-step sequential synthesis for the undergraduate organic chemistry laboratory has been
developed that produces a commercially and biologically important N-phenylmaleimide in two-
steps.
• The product is then utilized as the dienophile in a Diels–Alder reaction with 2,5-dimethylfuran to
produce a cycloadduct that also has potential biological applications. Students were excited by
the drastic color change in the amine acylation step.
• Students were intrigued to synthesize an expensive commercial product (N-(4-
chlorophenyl)maleimide) for a fraction of its commercial price. Since synthesis is a major
emphasis in the Organic II curriculum, students enjoyed performing a sequential synthesis in the
laboratory.
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7. Recommendations and perspectives R G Á N IC A 14

• To carry out the necessary research to adapt the synthesis processes that could
not be carried out to the organic chemistry students' laboratory.
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Thank you very much for your

attention