Synthesis of Coumarin

Now that we know how to identify a coumarin based on its structure, let's talk about how it's
made synthetically. (Note: coumarin and derivatives of coumarin can be isolated from plant
sources in nature but here we are going to focus on man-made methods of its preparation.)

Pechmann Condensation
One of the most popular methods of making coumarins is through what's called a Pechmann
condensation reaction. This reaction is of great utility since it utilizes cheap and commercially
available chemical building blocks. The Pechmann condensation involves taking phenol and
reacting it with ethyl acetoacetate in the presence of a catalyst (usually aluminum chloride is
used). The reaction is called a 'condensation' because literally our two reactant molecules
condense with one another to form our single product molecule. Once the condensation
happens, we get our coumarin product!

Kostanecki Acylation
Another popular method of making coumarins is by a reaction called the Kostanecki acylation,
which involves the use of an Ortho-hydroxyaryl ketone (an aromatic ketone with an -OH group
adjacent to it) with an anhydride of some sort. Much like the Pechmann condensation, this
transformation is a great way to make coumarins because it has pretty mild reaction conditions
and uses cheap and abundant starting materials.
Note: in this reaction any anhydride can be used, which is why we use the 'R' group designation
for the anhydride reactant.

Important Coumarin Derivatives

Let's now take our attention to a couple of the more important derivatives of coumarin. These
molecules contain our coumarin core structure, but also have some other groups attached to it.
This is why we call them derivatives because they are derived from coumarin itself. By far, one of
the most publicized coumarin derivatives is called warfarin. Warfarin is a molecule that's used as
a blood thinning agent to help prevent blood clots and prevent stroke. Notice the coumarin
skeleton highlighted in red in the structure of warfarin.
 Preparation, reaction and reaction condition for the preparation of coumarin derivatives
Coumarin derivatives can be prepared by a variety of synthetic methods, including cyclization
reactions, condensation reactions, and substitution reactions. Here is an example of a general
method for the synthesis of coumarin derivatives through a cyclization reaction:

Reactants:

 Salicylaldehyde or substituted salicylaldehyde

 Acetic anhydride
 Sodium acetate
 Ethanol or another suitable solvent

Reaction:

1. Salicylaldehyde or a substituted salicylaldehyde is mixed with acetic anhydride and sodium

acetate in ethanol or another suitable solvent.
2. The mixture is heated under reflux for several hours, allowing for cyclization to occur.
3. After the reaction is complete, the mixture is cooled and the product is isolated by filtration or
extraction.
4. The crude product is typically purified by recrystallization or chromatography.

The general reaction equation for the synthesis of coumarin derivatives through cyclization is:

R-OH + O=C(CH3)2O + NaOAc → R-CO-C6H4-CH=CH-CO + NaOOCCH3 + H2O

where R is a substituent on the salicylaldehyde ring.

Note that the specific reaction conditions and reactants used may vary depending on the specific
coumarin derivative being prepared, and may require some optimization to maximize the yield
and purity of the final product.