Question

Show how to use alkylation or acylation of an enamine to convert acetophenone to the following compounds. (a) CC(=O)CC(=O)c1ccccc1 (b) CC(=O)CCC(=O)c1ccccc1 (c) CCOC(=O)CCC(=O)c1ccccc1

Short answer

Question: Describe the basic process of synthesizing the following compounds from acetophenone through alkylation or acylation of an enamine: (a) CC(=O)CC(=O)c1ccccc1, (b) CC(=O)CCC(=O)c1ccccc1, and (c) CCOC(=O)CCC(=O)c1ccccc1. Answer: The synthesis process for the given compounds from acetophenone through enamine alkylation or acylation consists of three fundamental steps: (1) formation of enamine intermediate by reacting acetophenone with an amine like pyrrolidine, (2) alkylation or acylation of the enamine intermediate with an alkylating reagent, which varies depending on the desired product, and (3) hydrolysis of the enamine by heating with an aqueous acid, regenerating the ketone and obtaining the desired product.

Step-by-step solution

Formation of Enamine Intermediate

In order to form the desired Aldol product, we need to begin with the formation of the enamine intermediate. We start by reacting acetophenone with a suitable amine (such as pyrrolidine) in the presence of a mild acid catalyst to obtain the enamine of acetophenone.

Alkylation of Enamine Intermediate

Next, we react the enamine intermediate with the alkylating reagent, in this case, ethyl bromoacetate. This allows the enamine to attack the electrophilic center of the ethyl bromoacetate, leading to the addition of a carbonyl group on the desired position (the α-carbon of acetophenone).

Hydrolysis of Enamine

Finally, we hydrolyze the enamine by heating with an aqueous acid, regenerating the ketone and obtaining the desired product. (b) Synthesis of CC(=O)CCC(=O)c1ccccc1:

Formation of Enamine Intermediate

Similar to the above case, we start by reacting acetophenone with pyrrolidine in the presence of a mild acid catalyst to obtain the enamine of acetophenone.

Alkylation of Enamine Intermediate

In this case, we are going to use a different reactant—propionyl chloride—as our alkylating reagent. The enamine will attack the electrophilic carbon of propionyl chloride, leading to the α-alkylation on the acetophenone resulting in the addition of the carbonyl group at the α-carbon.

Hydrolysis of Enamine

We then hydrolyze the enamine by heating with an aqueous acid, regenerating the ketone and obtaining our desired product. (c) Synthesis of CCOC(=O)CCC(=O)c1ccccc1:

Formation of Enamine Intermediate

Again, we react acetophenone with pyrrolidine in the presence of a mild acid catalyst to obtain the enamine of acetophenone.

Alkylation of Enamine Intermediate

In this case, our alkylating reagent will be ethyl 3-oxobutanoate. The enamine will react with the ethyl 3-oxobutanoate, attacking the electrophilic carbon and leading to the α-alkylation on the acetophenone.

Hydrolysis of Enamine

As before, we hydrolyze the enamine by heating with an aqueous acid, regenerating the ketone and obtaining the desired product. Each synthesis is comprised of the same three steps, but with different alkylating reagents. This showcases how the choice of reactants can lead to different products using the same fundamental process of enamine alkylation or acylation.