The preparation of amides is one of the most common reactions in organic synthesis and a key reaction for the preparation of peptide drugs and nucleic acid drugs in recent years. The reaction for synthesizing amide bonds is very extensive in the laboratory, and there are currently many types of reactions for synthesizing amides. Today, let’s summarize the methods for synthesizing amides together.
Amide Condensation for Amide Preparation
Amide condensation reaction is one of the most commonly used methods in organic chemistry for preparing amide bonds, which is both common and mild.
The most commonly used condensing agents for preparing amides include the following:
- DCC, EDCl, DIC, and other carbodiimide condensing agents
- HATU, HBTU, HCTU, TBTU, and other uronium salt condensing agents
- BOP, PyBOP, and other uronium salt condensing agents
- CDI (N,N’-carbonyldiimidazole)
The use of different condensing agents brings significant changes to the reaction. Of course, the choice of base and activating agent, the order of addition of reactants, changes in temperature, and control of reaction time all have different degrees of influence on the condensation of acids to amides. Before conducting the reaction, the reaction process and monitoring should be carefully handled to ensure that the reaction is both clean and high-yielding.
Acid Halide Method
The reaction of acid halides (acyl chlorides, acyl bromides, and acyl fluorides) with ammonia or amines is the simplest and most commonly used method for synthesizing amides.
Acyl chlorides and acyl bromides can readily acylate aliphatic and aromatic amines to form amides with relatively high yields. However, acyl fluorides are more stable towards water and other nucleophilic reagents. The reaction of acyl chlorides and acyl bromides with amines is exothermic and sometimes even highly vigorous, so the reaction is usually carried out under cooling, and a certain amount of solvent can be used to slow down the reaction rate.
Common solvents include dichloroethane, ether, carbon tetrachloride, toluene, etc. Since hydrogen halide is generated during the reaction, it needs to be removed with a base to prevent it from forming salts with the amine. Both organic and inorganic bases can be used for such reactions, with commonly used organic bases including triethylamine, pyridine, etc., and commonly used inorganic bases including Na2CO3, NaHCO3, K2CO3, NaOH, KOH, etc.
We have found that many reactions are cleaner and easier to handle when using inorganic bases. For some sterically hindered and less reactive aryl amines, even using acyl chlorides may not lead to the desired reaction. In such cases, a catalyst such as DMAP may be added, or sometimes the amide can be obtained directly from the reaction of the amine and acyl chloride at high temperature without adding any base.
Acyl chlorides are mainly prepared by thionyl chloride and phosphorus oxychloride. For substrates with high boiling points, thionyl chloride is the most suitable reagent; for substrates with low boiling points, phosphorus oxychloride is more convenient because they can be easily distilled.
For α-amino acids, since the corresponding acyl chlorides decompose upon heating, they are generally not prepared using thionyl chloride and phosphorus oxychloride. When there are acid-sensitive functional groups in the molecule, thionyl chloride cannot be used, and equivalent amounts of acyl chloride and base (a small amount of DMF has a good catalytic effect) are usually used for one-pot acylation reaction. Recently, it has also been reported in the literature that trichloroacetonitrile can be used in one pot to convert acids into acyl chlorides in the presence of a base.
Since acyl chlorides are highly reactive, they are generally difficult to identify. Sometimes, to determine whether acyl chloride has been generated, a small amount of benzylamine or methanol is added, and the extent of the reaction is confirmed by TLC. Additionally, the solvent can be evaporated and confirmed by HPLC, LC-MS, or NMR.
α-Amino acyl chlorides are generally synthesized by the above two methods. Aromatic acyl chlorides are generally more stable than alkyl acyl chlorides. For example, benzoyl chloride takes nearly half an hour to decompose in water.
Ester Exchange to Amide
The reaction of esters with ammonia yields amides conveniently. This is one of the commonly used methods for preparing amides in the laboratory. Especially in the synthesis of cyclic compounds, directly converting the oxygen of esters into a secondary amine provides more operational space.
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Acyl Azide Method
Acyl azide is also a relatively mild acylation reagent. Due to its lack of causing racemization of optically active substances during reaction and its stability to water and other nucleophilic reagents, it is commonly used in the synthesis of peptides and compound libraries. However, due to its low reactivity, acyl azide is not suitable for amines with steric hindrance and low nucleophilicity.
Cyanide Hydrolysis Synthesis of Amides
Nitriles can be hydrolyzed to primary amides. Since primary amides can further hydrolyze to carboxylic acids, the hydrolysis conditions need to be controlled. Currently, there are many reported methods, sometimes requiring the selection of acidic, basic, or neutral hydrolysis conditions based on the substrate’s characteristics. As for neutral conditions, literature also reports the use of nickel or palladium catalysts.
Acidic hydrolysis: Cyanides attached to saturated carbons can conveniently hydrolyze into amides in acidic conditions and can easily further hydrolyze into acids under more severe conditions. However, hydrolysis conditions for vinyl or aryl nitriles require more severity, usually necessitating strong acid conditions, and generally do not further hydrolyze.
Basic hydrolysis: Under basic conditions, hydrolysis of nitriles to primary amides can be reliably achieved using methods involving hydrogen peroxide oxidation at room temperature for a short time. Systems such as NaOH(aq.)-CH2Cl2 and DMSO-K2CO3 can be used for various nitrile hydrolysis to primary amides.
Preparation of Amides Using Anhydrides
Anhydrides, like acyl halides, can also act as acylating agents for amines, but the reactivity of anhydrides is weaker than that of the corresponding acyl halides, so the reaction rate with amines is slower.
Primary and secondary amines can react smoothly with acetic anhydride, but fatty primary amines often yield mixtures of N-acetylation and N,N-diacylation, the ratio of which depends on the structure of the primary amine. When the primary amine has the structure RCH2NH2, N,N-diacylation products are predominantly formed, whereas when it has the structure RR1CHNH2, a mixture of N-acetylation is obtained. When the primary amine has the structure RR1R2CNH2, only N-acetylation products are obtained.
Ritter Reaction
Reaction to prepare amides from alcohols and nitriles in a strong acid environment.
The tertiary carbocation adds to the nitrogen atom of the nitrile to form a nitrile salt, which upon hydrolysis with water yields the corresponding amide. Generally, compounds capable of generating carbocations can undergo such reactions. Since alcohols or olefins react under heated conditions with concentrated sulfuric acid or other strong acids, nitriles stable under these conditions can be used for such reactions. These reactions proceed by the reaction of the nitrile and acid in a solvent, but for acetonitrile, the reaction can be carried out directly in acetonitrile, while for other more complex, higher-boiling substrates, dilution with glacial acetic acid is usually employed.
Chan-Lam Coupling Reaction
Amide compounds or nitriles react with boronic acids to yield multiply substituted amides.
Overman Rearrangement
A reaction where the allylic trichloroacetimidate is transformed into the allylic trichloroacetamide through a 1,3-position exchange of the alkene, subsequently converting allylic alcohol into allylic amine.
Passerini Reaction
A three-component condensation reaction involving a carboxylic acid, an isocyanide, and a carbonyl compound to yield α-acyloxyamides. This reaction is similar to the Ugi reaction.
Ugi Reaction
A four-component condensation reaction involving a carboxylic acid, an isocyanide, an amine, and a carbonyl compound to yield diacylamides (dipeptides).
Schotten-Baumann Reaction
In 1884, C. Schotten reported the efficient synthesis of N-benzoylpiperidine from pyridine and benzoyl chloride in the presence of sodium hydroxide in water. In 1886, E. Baumann found that under the same reaction conditions, the reaction of alcohol with benzoyl chloride yields benzoate. When alcohol and benzoyl chloride are mixed in water, followed by the addition of sodium hydroxide solution, the ester product can rapidly precipitate in high yields. Baumann also found that polyhydroxy compounds such as glucose and glycerol can also undergo benzoylation using this reaction. The reaction involving the preparation of esters or amides from alcohols or amines with acid halides or anhydrides in the presence of a base in an aqueous solution is termed the Schotten-Baumann reaction.
Polonovski Reaction
A rearrangement reaction where the nitrogen oxide of a tertiary amine is treated with an active reagent (such as acetic anhydride), leading to the formation of N,N-disubstituted acetamide and an aldehyde.
Schmidt Rearrangement
The Schmidt reaction refers to the rearrangement reaction where azides or diazo compounds react under acid catalysis with electrophilic reagents (carbonyl compounds, tertiary alcohols, and alkenes), releasing nitrogen gas to yield amines, nitriles, amides, or imines.
Beckmann Rearrangement
The rearrangement reaction of oximes to yield amides under acid catalysis.
Wolff Rearrangement
A reaction where α-diazoketones rearrange to yield enones. Enones are important organic intermediates. They can react with water to produce carboxylic acids, with alcohols to produce esters, with amines to produce amides, and undergo Staudinger enone ring addition to synthesize various tetrahydrofuran compounds (can undergo [2 + 2] cycloaddition with alkenes, aldehydes/ketones, and imines to yield cyclobutanones, β-lactones, and β-lactams).
Eschenmoser–Claisen Amide Ketone Rearrangement
The rearrangement reaction of allylic alcohol compounds and N,N-dimethylacetamide dimethylacetal under heating conditions to yield γ,δ-unsaturated amides. Since Eschenmoser discovered this reaction based on Meerwein’s research on amide exchange, this reaction is also known as the Meerwein-Eschenmoser-Claisen rearrangement.
Goldberg Coupling Reaction
Reaction of amide compounds with aromatic halides to yield multiply substituted amides.
Buchwald-Hartwig Reaction
Reaction of amide compounds with aromatic halides to yield multiply substituted amides.
Copper-Catalyzed Reaction of Triaryl Bismuth and Amides
Recently, there have been some reports on bismuth salt-mediated arylation, with better yields compared to the corresponding boronic acids. The reaction conditions are milder and can be carried out at room temperature. Apart from simple amides, bismuth salts can also be used for the arylation of acyl hydrazides, ureas, and sulfonamides. Since bismuth salts are stable in air, the reaction operation is convenient. However, triaryl bismuth generally needs to be synthesized, and it is difficult to synthesize when there are strong electron-withdrawing groups on the aromatic ring, which limits the use of triaryl bismuth for arylation. When there is no substituent on the N of the amide, a diarylation product may occur, so triaryl bismuth is mostly used for the arylation of lactams and secondary amides. When the substrate is sterically hindered, chloroform can be used as the solvent to increase the reaction temperature, resulting in higher conversion rates.
Kinugasa β-Lactam Synthesis Reaction
Breckport β-Lactam Synthesis
Davies Iron Chiral Auxiliary
Alper Carbonylation Reaction
Halogenated aromatic compounds containing fatty amine, vinylamine, and vinyl nitrogen heterocycles react with carbon monoxide under Pd, Ru, or Rh catalysts to undergo carbonyl insertion and form cyclic amides.
Snieckus Aminoformate Rearrangement
The aminoformate-O-aryl ester undergoes ortho-metalation, and then the aminoformyl group migrates from oxygen to the neighboring carbon to yield ortho-hydroxybenzamides. Similar to the Hauser–Beak reaction. Reaction can also occur at closely located sites.
Common Reagent–Mukaiyama Reagent
The reaction of carboxylic acids with imines to generate β-lactams promoted by CMPI also has significant synthetic value (Equation 6), but polymeric loaded reagents cannot undergo this reaction. If the chlorine atom on the pyridine ring is replaced with an iodine atom to generate the modified Mukaiyama reagent, satisfactory results can also be obtained under ultrasonic conditions.
Atherton-Todd Reaction for Phosphoramidate Synthesis
The P-H bond of diethyl phosphite reacts with carbon tetrachloride under mild basic conditions, converting the P-H bond into a P-Cl bond, followed by reaction with an amine to synthesize phosphoramidates.
Carbonylation Reaction to Prepare Carboxylic Acids and Derivatives
Carbonylation reactions can also be used to prepare amides.
Minisci Reaction
