Question

Following is a retrosynthetic analysis for the synthesis of the herbicide (S)-Metolachlor from 2-ethyl-6-methylaniline, chloroacetic acid, acetone, and methanol. Show reagents and experimental conditions for the synthesis of Metolachlor from these four organic starting materials. Your synthesis will most likely give a racemic mixture. The chiral catalyst used by Novartis for reduction in Step 2 gives \(80 \%\) enantiomeric excess of the \(S\) enantiomer.

Short answer

In summary, the synthesis of (S)-metolachlor is achieved through a series of four steps: 1. Acylation of 2-ethyl-6-methylaniline with chloroacetic acid using a dehydrating agent such as POCl3 or SOCl2. 2. Reduction of the amide to amine using a chiral Rhodium catalyst and hydrogen gas to achieve 80% enantiomeric excess of the S enantiomer. 3. Formation of enamine by reacting the amino-acid product with acetone under basic conditions using sodium hydroxide (NaOH) as a base. 4. Alkylation of the enamine with chloromethane (CH3Cl) in the presence of a basic catalyst like potassium carbonate (K2CO3). The final product is a racemic mixture of metolachlor with an 80% enantiomeric excess of the S enantiomer.

Step-by-step solution

Acylation of 2-ethyl-6-methylaniline with chloroacetic acid

First, react 2-ethyl-6-methylaniline with chloroacetic acid in the presence of a dehydrating agent such as phosphorus oxychloride (POCl3) or thionyl chloride (SOCl2). This reaction will form the amide and remove one molecule of hydrochloric acid (HCl). 2-ethyl-6-methylaniline + chloroacetic acid \(\xrightarrow[]{POCl_3\ or\ SOCl_2}\) [(R)-2-ethyl-6-methylanilino]acetyl Chloride

Reduction of the amide to amine

Next, reduce the amide to an amine using a chiral catalyst, like Rhodium catalyst, to help achieve an 80% enantiomeric excess of the S enantiomer. The reducing agent used in this step is usually hydrogen gas (H2). [(R)-2-ethyl-6-methylanilino]acetyl Chloride + H2 \(\xrightarrow[]{Rhodium\ catalyst}\) (S)-[(R)-2-ethyl-6-methylanilino]-acetic acid

Formation of enamine

Now, form the enamine by reacting the amino-acid product obtained in step 2 with acetone under basic conditions. This can be achieved by using sodium hydroxide (NaOH) as a base. (S)-[(R)-2-ethyl-6-methylanilino]-acetic acid + acetone \(\xrightarrow[]{NaOH}\) (S)-1'-ethyl-2'-methyl-6'-methylaniline-acetonide

Alkylation of enamine

Finally, alkylate the enamine formed in step 3 with chloromethane (CH3Cl) in the presence of a basic catalyst like potassium carbonate (K2CO3). This alkylation reaction will lead to the formation of the desired product, (S)-metolachlor. (S)-1'-ethyl-2'-methyl-6'-methylaniline-acetonide + CH3Cl \(\xrightarrow[]{K_2CO_3}\) (S)-Metolachlor The final product of this synthesis is a racemic mixture of metolachlor, with an 80% enantiomeric excess of the S enantiomer due to the chiral catalyst used in step 2.

Key concepts

Retrosynthetic Analysis

Retrosynthetic analysis is a strategy in organic chemistry that involves deconstructing complex molecules into simpler ones to understand how they might be synthesized. This approach is akin to solving a puzzle by working backward from the end picture to the starting pieces.

In the case of synthesizing (S)-Metolachlor, a common herbicide, it is crucial to recognize the individual building blocks like 2-ethyl-6-methylaniline, chloroacetic acid, acetone, and methanol and plan their assembly in a sequential manner. This strategy ensures that chemists can systematically approach a complex synthesis by considering how each step and its specific conditions contribute to the overall construction of the molecule.

Enantiomeric Excess

Enantiomeric excess is a critical concept in the field of stereochemistry, particularly when dealing with chiral molecules - those that have a non-superimposable mirror image. It is a quantitative measure of the purity of a particular enantiomer in a mixture relative to the other enantiomer.

In synthesis, if a racemic mixture (an equal mix of enantiomers) forms, it may not be useful in applications where chirality is important, such as in the pharmaceutical industry. For the synthesis of (S)-Metolachlor, which ideally requires only the S-enantiomer, an 80% enantiomeric excess means that the mixture consists of 80% of the desired S-enantiomer and only 20% of the R-enantiomer. Such selectivity is often achieved through the use of chiral catalysts in the synthesis process.

Chiral Catalysts

Chiral catalysts are specialized molecules that can induce chirality or enhance the selectivity towards a particular enantiomer in a chemical reaction. They are indispensable tools for achieving high enantiomeric excess in the synthesis of chiral compounds.

In the synthesis of (S)-Metolachlor, a Rhodium-based chiral catalyst is used in the second step to selectively reduce the amide to the amine with a preference for the S-enantiomer. These catalysts work by providing an asymmetric environment for the reaction, which influences the path the reactants take, ultimately leading to an excess of one enantiomer over the other. The ability of these catalysts to 'steer' reactions towards a single enantiomer is crucial for producing substances with the desired biological activity.

Organic Reaction Conditions

Organic reaction conditions are the specific parameters under which a chemical reaction is carried out, including temperature, pressure, solvent, concentration of reactants, and any catalysts or additives. These conditions can significantly impact the course and the outcome of a reaction.

For the multistep process of creating (S)-Metolachlor, each step requires carefully chosen conditions. For example, the acylation of 2-ethyl-6-methylaniline with chloroacetic acid uses a dehydrating agent like POCl3 or SOCl2, whereas the reduction step not only involves a chiral catalyst but also a reducing agent like H2 gas. The conditions are tailored in each step to favor the formation of the desired product, an essential aspect of synthesizing complex molecules like (S)-Metolachlor.