We have seen that attempts to alkylate simple aldehydes, ketones, and esters may be rendered ineffective by the occurrence of competing reactions, notably aldol and Claisen condensations as well as Sn2 and E2 reactions. Deprotonation of aldehydes, ketones, and esters with LDA allows for direct alkylation of these compounds, while deprotonation of dithiane derivatives of aldehydes offers an indirect method for replacing the aldehydic proton with an alkyl group. In this topic we will consider another approach to alkylation of aldehydes and ketones, namely the Mannich reaction. The development of this approach, in the early 1900s, was guided in some measure by insights into the biochemical pathways that plants use to make natural products called secondary metabolites. Secondary metabolites are compounds that an organism produces that are not essential to its survival, i.e. unlike primary metabolites, secondary metabolites are not used in the synthesis of the proteins or lipids, or nucleic acids, or energy that an organism requires for survival. However, it is now clear that these natural products are beneficial, if not essential, to the organisms that produce them.
Probably the most familiar group of secondary metabolites is the pheromones. Plants and insects alike release these compounds as a form of chemical communication, conveying simple messages such as "danger", and "this way to lunch", or "Poison! Eat at your own risk".
In plants, alkaloids constitute another group of secondary metabolites. Alkaloids are natural products that contain an amino group. The name is derived from the fact that aqueous solutions of these compounds are slightly basic, i.e. alkaline, due to the presence of the amino group. The reactions that produce alkaloids generally involve the secondary metabolism of amino acids. Figure 1 presents a highly abbreviated picture of the biosynthesis of nicotine from the amino acid ornithine.
An Abbreviated Biosynthesis of Nicotine
In the first step of this sequence the C-2 amino group of ornithine adds to the carbonyl group of pyridoxal phosphate to form an imine. (The pyridoxal phosphate is bound to an enzyme, which is not shown in this diagram.) Decarboxylation followed by tautomerization generates an isomeric imine which undergoes hydrolysis to produce 4-aminobutanal along with an enamine that is converted back to pyridoxal phosphate by hydrolysis. The 4-aminobutanal exists in equilibrium with the 5-membered heterocycle D1-pyrrolideine. As emphasized in the red box, an enolate ion derived from acetoacetyl coenzyme A adds to the protonated imine group of this 5-membered ring. Subsequent reactions complete the biosynthesis of nicotine. It is the addition of the enolate ion to the iminium ion that led to the development of the Mannich reaction. Synthetic methodologies that are designed in this way are referred to as biomimetic reactions. The Mannich reaction was the first biomimetic synthesis to be developed.
The Mannich Reaction
So what is the Mannich reaction? In its simplest form, it involves the nucleophilic addition of an enol to an iminium ion formed by the reaction of formaldehyde with a secondary amine. Equation 11 provides a specific example.
Exercise 1 Draw the structure of the product expected from each of the following reactions:
The Mannich reaction involves several acid-catalysed equilibria. Like the aldol condensation, the success of the Mannich reaction depends on being able to generate both nucleophilic and electrophilic carbons in the reaction mixture at the same time. Figure 2 shows how this is done in the reaction of dimethylamine, formaldehyde, and acetone.
The Mannich Mechanism
When performing a Mannich reaction, it is common practice to use the hydrochloride salt of the amine as one of the starting materials. In aqueous solution the salt exists in equilibrium with the free amine. The proton that accompanies the formation of the free amine in Equilibrium 1 is available to protonate other reactants in the solution (Equilibria 2 and 3). Addition of the free amine to a protonated molecule of formaldehyde leads to the formation of the iminium ion shown at the right of Equilibria 4. The enol of acetone then adds to the carbon atom of the iminium ion in Equilibrium 5. Loss of a proton from the oxonium ion intermediate during the work-up of the reaction yields the final product.
Exercise 2 Phenol,, may be regarded as an enol. Draw the keto tautomer of phenol.
Exercise 3 Predict the product of the following Mannich reaction:
(Don't forget- the enol form of phenol is more stable than the keto form.)
Equations 2 and 3 provide two examples of applications of the Mannich reaction in the synthesis of natural products. Equation 4 illustrates a transformation that was achieved in 1917 and is the first example of a biomimetic synthesis.
Naturally occuring atropine is a toxic alkaloid isolated from the plant Atropa belladonna, commonly called nightshade.
Cocaine is a close structural analog of atropine, and the syntheses of these two alkaloids involve the same basic approach.
Finally, Figure 3 describes an interesting example of an intramolecular Mannich reaction that was used in the total synthesis of strychnine.
These Alkaloids Are Killing Me
The essential chemistry to consider in Figure 3 begins with the reaction of the secondary amine with formaldehyde. Under the conditions of the reaction, the resulting iminium ion intermediate was not isolated. Rather it underwent a thermal rearrangement, as indicated by the red arrows, to produce a new intermediate that contained an enol and an iminium ion in close proximity. As the blue arrows suggest, these electronically complementary groups reacted spontaneously to form the tricyclic structure shown at the lower right of the figure. The rest of the molecule was elaborated in a series of steps that are not relevant to this discussion. The cyclohexane ring of the final product which arose from the intramolecular Mannich reaction is highlighted in blue.