Mannich Reaction Overview

The Mannich Reaction

• The Mannich reaction is an aminoalkylation reaction.
• It involves the condensation of an enolizable carbonyl compound with a nonenolizable aldehyde (like formaldehyde) and ammonia, or a primary or secondary amine.
• This reaction forms a β-aminocarbonyl compound, often called a Mannich base.

Background

• Carl Mannich was a German chemist (March 8, 1877 – March 5, 1947).
• He was a professor of pharmaceutical chemistry at the University of Berlin from 1927 to 1943.
• His expertise included keto bases, alcohols, piperidine derivatives, papaverine, lactones, and digitalis glycosides.

Background (Mechanism)

• The reaction is best performed with methyl ketones.
• Aldehydes other than formaldehyde can be used.
• Diethyl amine - HCl is often used in excess (used as a base).
• Other secondary amines can replace diethylamine.
• A variety of R groups can be incorporated.

Mechanism

• Complex chemical reaction mechanisms are shown.

Limitations

• The Mannich reaction has limited applications.
• It often creates undesired side products.
• It often struggles to control regio- and stereoselectivity.

Modifications

• Preformed Mannich reagents increase reaction speed & efficiency.
• Using a higher electrophile concentration lowers reaction temperatures, and decreases reaction times.
• Sensitive substrates produce fewer side reactions.
• Replacing the carbonyl component with a reactive synthetic equivalent like an enolate improves efficiency.
• This reaction has an extended spectrum of application.

Modifications (Cont.)

• Imines
• Aminals
• N,O-acetals
• Benzotriazole aminals
• Iminium salts
• Intermolecular amino-alkylation

Modifications (cont.)

• Carbonyl compounds (with iminium salts)
• Enolates (with N,O acetals)
• Boron enol ethers (with aminals)
• Silyl enol ethers (with methylene iminium salts)

Applications

• Used in the synthesis of pharmaceuticals, natural products, organic materials, and nanomaterials.
• Used to create tazarotene (a psoriasis & acne treatment) and SIB-1508Y (also known as Altinicline, a nicotinic receptor agonist).
• Applicable in alkynylation, enynes, and enediynes reactions.

Applications (Medical Compounds)

• Produces various medicinally important compounds, like fluoxetine and Tramadol.

Applications (Natural Product Synthesis)

• Used in the synthesis of natural products.
• Produces compounds like epibatidine, ferruginine, and anatoxin.

Wittig Reaction

• A chemical reaction to synthesize alkenes.
• Involves reacting an aldehyde or ketone with a triphenylphosphonium ylide (a Wittig reagent).
• The product is an alkene and triphenylphosphine oxide.
• This reaction is nucleophilic addition then elimination.

Wittig Reaction (Mechanism)

• The reaction includes several steps.
• Preparing the ylide through a reaction of triphenyl phosphine and alkyl halide.
• Using organolithium compounds for deprotonation to create the ylide.

Wittig Reaction (Mechanism - cont.)

• Alkene formation from carbonyl compounds and phosphonium ylides.
• This reaction primarily involves proposed betaine and/or oxaphosphetane intermediates.
• The choice of ylide, carbonyl compound, and reaction conditions can control the stereoselectivity of the reaction.
• If the ylide is replaced with a phosphine oxide carbanion, it is referred to as the Horner reaction.
• If the ylide is replaced with a phosphonate carbanion, it is referred to as the Horner-Wadsworth-Emmons reaction.

General Wittig Reaction

• This reaction uses a carbonyl compound as an electrophile, attacked by the phosphorus ylide.
• The Wittig reaction complements the aldol condensation.
• The aldol condensation produces enones.
• Wittig reactions are more flexible as the product carbonyl does not need to have an attached carbonyl.

Sonogashira Reaction

• A cross-coupling reaction in organic synthesis to create carbon-carbon bonds in terminal alkynes and aryl or vinyl halides.
• Pd and Cu catalysts are used simultaneously.

Sonogashira Reaction: Conditions and Solvents

• Conducted under mild conditions (like room temperature and in aqueous media).
• Typically uses amines such as diethylamine.
• Diethylamine also acts as a solvent that neutralizes the hydrogen halide byproduct of this coupling reaction.

Sonogashira Reaction: Catalysts

• Needs zerovalent palladium complexes (like Pd(PPh3)4 or Pd(PPh3)2Cl2).
• Bidentate ligand catalysts (like Pd(dppe)Cl, Pd(dppp)Cl2, and Pd(dppf)Cl2) are often used.
• Needs copper(I) halide co-catalysts like copper iodide.
• Palladium(II) is often used as a pre-catalyst.

Sonogashira Reaction: Mechanism

• A detailed description of the Pd and Cu catalytic cycle is present.

Sonogashira Reaction: Complications

• Specific amines must be added in excess as a reactant or solvent for the reaction process, as piperidine, morpholine, and diisopropylamine.
• The equilibrium constant depends on R, X (factors for basicity) and the steric hindrance of the amine.

Sonogashira Reaction: Applications

• Used in synthesis of pharmaceuticals, natural products, organic materials, and nanomaterials.
• Includes the synthesis of tazarotene (psoriasis and acne treatment), and SIB-1508Y (nicotinic receptor agonist).
• Also used in alkynylation reactions, enynes, and enediynes.

Sonogashira Reaction: Limitations

• Copper co-catalysts form alkyne dimers, which is unwanted.
• The presence of copper leads to Glaser coupling.
• To prevent this, reactions need to be conducted in an inert atmosphere.
• Copper-free Sonogashira reaction variations have recently been developed.

Explore the Mannich reaction, an important aminoalkylation process that forms β-aminocarbonyl compounds. Learn about the significant contributions of Carl Mannich and the key components and mechanisms involved in this reaction. Understand its applications and limitations in organic chemistry.