Question

One potential synthesis of the anti-inflammatory and analgesic drug nabumetone is chloromethylation (Problem 22.48) of 2 -methoxynaphthalene followed by an acetoacetic ester synthesis (Section 19.6). (a) Account for the regioselectivity of chloromethylation at carbon 6 rather than at carbon 5 or 7 . (b) Show steps in the acetoacetic ester synthesis by which the synthesis of nabumetone is completed.

Short answer

Question: Explain the regioselectivity of chloromethylation at C6 in the synthesis of nabumetone and provide the steps involved in the acetoacetic ester synthesis to complete the synthesis of the drug. Answer: The regioselectivity of chloromethylation at C6 in the synthesis of nabumetone is due to increased electron density at C6 from resonance effects and the electron-donating nature of the methoxy group at C2. The acetoacetic ester synthesis involves three steps: (a) formation of the enolate ion by deprotonation, (b) alkylation of the enolate ion with ethylacetoacetate, and (c) hydrolysis and decarboxylation of the enolate alkylated product to form nabumetone.

Step-by-step solution

Explaining the regioselectivity of chloromethylation at C6

In the chloromethylation of 2-methoxynaphthalene, the reaction is regioselective, favoring the substitution at C6 rather than C5 or C7. This is due to two factors: first, because C6 has both C5 and C7 as ortho-positions, which increases the electron density around C6 due to the resonance effect, making it a more suitable electrophilic site. Secondly, because the methoxy group at C2 acts as an electron-donating group through a resonance effect, and this increases the electron density at the para-positions (C6 and C7) more than the ortho-positions (C3 and C5). Consequently, the reaction prefers C6 over other carbons.

Acetoacetic ester synthesis

Now, we will show the steps involved in the acetoacetic ester synthesis to complete the synthesis of nabumetone. (a) Formation of the enolate ion by deprotonation: Treat the chloromethylated product from step 1 (6-chloromethyl-2-methoxynaphthalene) with a strong base such as sodium ethoxide (\text{C}_{2}\text{H}_{5}\text{ONa}). The base abstracts the acidic proton from the carbon adjacent to the ketone group (α-carbon) to form the enolate ion. (b) Alkylation of the enolate ion: The enolate ion formed in step (a) reacts with the electrophile, ethylacetoacetate, at the α-carbon to form a new C-C bond: \text{Enolate Ion} + \text{CH}_{3}\text{COCH}_{2}\text{COOC}_{2}\text{H}_{5} \longrightarrow \text{Enolate Alkylated Product} (c) Hydrolysis and decarboxylation: Finally, we treat the enolate alkylated product from step (b) with an acid to hydrolyze the ester group and induce decarboxylation, leading to the formation of nabumetone: \text{Enolate Alkylated Product} + \text{H}_{3}\text{O}^{+} \longrightarrow \text{Nabumetone} + \text{CO}_{2} + \text{C}_{2}\text{H}_{5}\text{OH} These are the steps involved in the acetoacetic ester synthesis for the completion of nabumetone synthesis.

Key concepts

Regioselectivity of Chloromethylation

When it comes to the chloromethylation of aromatic compounds, regioselectivity dictates where the chloromethyl group will attach to the aromatic ring. The reaction is influenced by the electronic effects of substituents already present on the ring. For 2-methoxynaphthalene, the significance lies in the methoxy group, which is an electron-donating group through resonance and inductive effects.

During this process, the methoxy group enhances the electron density at certain positions of the naphthalene ring, primarily the para- and ortho-positions relative to itself. This promotion of electron-rich areas makes certain carbons more attractive to electrophiles. Specifically, the sixth carbon (C6) is favored due to a higher electron density that is not only influenced by the adjacent carbons (ortho effect) but also by being at a para position relative to the methoxy group. This synergy leads to a preference for electrophilic attack at C6 over C5 or C7.

Synthesis of Nabumetone

Nabumetone is a non-steroidal anti-inflammatory drug with intriguing synthesis beginning with chloromethylated 2-methoxynaphthalene. The formation of nabumetone proceeds through steps involving the creation of an enolate ion which further undergoes alkylation, followed by hydrolysis and decarboxylation to unravel the final product.

After the regioselective chloromethylation positions the chloromethyl group properly, the synthesis builds on this by constructing the acetoacetic ester framework. Leveraging the reactivity of the enolate ion, it's possible to introduce the acetoacetate side chain, which after subsequent reactions, elegantly transforms into nabumetone. Each intermediary step involves carefully controlled conditions ensuring that the desired transformations occur with the precision necessary to yield a potent pharmaceutical.

Enolate Ion Formation

Enolate ions are central to many organic reactions, acting as nucleophiles that can attack various electrophiles. Enolates form from carbonyl compounds when the hydrogen atoms bonded to the carbon adjacent to the carbonyl (the alpha carbon) are removed by a base. This deprotonation creates a resonance-stabilized anion.

The conditions under which the enolate forms are crucial since they determine the concentration and reactivity of the enolate ion. The choice of base, solvent, and temperature all influence whether the reaction will lean towards the kinetic or thermodynamic product. In the context of acetoacetic ester synthesis, a strong base like sodium ethoxide effectively abstracts the proton to form the enolate ion, enabling the subsequent steps needed for the creation of nabumetone.

Electrophilic Aromatic Substitution

Electrophilic aromatic substitution (EAS) is a method by which an aromatic ring undergoes reaction to replace a hydrogen atom with an electrophile. The aromatic system is rich in pi electrons and acts as a nucleophile, making it incredibly attractive to electron-deficient species, known as electrophiles.

In the context of creating medicines like nabumetone, EAS plays a crucial role. The initial step of introducing the chloromethyl group into 2-methoxynaphthalene is a classic EAS where regioselectivity is determined by the directing effects of existing substituents. Mastery of EAS allows chemists to manipulate aromatic compounds, installing various functionalities needed to achieve biological activity. Overall, EAS is not just a reaction mechanism; it is a valuable tool in the synthesis of complex molecules.