| Madelung indole synthesis | |
|---|---|
| Named after | Walter Madelung |
| Reaction type | Ring forming reaction |
| Identifiers | |
| RSC ontology ID | RXNO:0000511 |
In organic chemistry, Madelung synthesis is a chemical reaction that produces (substituted or unsubstituted) indoles by the intramolecular cyclization of N-phenylamides using strong base at high temperature. The Madelung synthesis was reported in 1912 by Walter Madelung, when he observed that 2-phenylindole was synthesized using N-benzoyl-o-toluidine and two equivalents of sodium ethoxide in a heated, airless reaction. Common reaction conditions include use of sodium or potassium alkoxide as base in hexane or tetrahydrofuran solvents, at temperatures ranging between 200–400 °C. A hydrolysis step is also required in the synthesis. The Madelung synthesis is important because it is one of few known reactions that produce indoles from a base-catalyzed thermal cyclization of N-acyl-o-toluidines.
Variants with other bases or additional substituents are possible, but the method is essentially confined to the preparation of 2-alkinylindoles (not easily accessible through electrophilic aromatic substitution) because of vigorous reaction conditions. A detailed reaction mechanism for the Madelung synthesis follows.
The reaction begins with the extraction of a hydrogen from the nitrogen of the amide substituent and the extraction of a benzylic hydrogen from the substituent ortho to the amide substituent by a strong base. Next, the carbanion resulting from the benzylic hydrogen extraction performs a nucleophilic attack on the electrophilic carbonyl carbon of the amide group. When this occurs, the pi-bond of the amide is converted into a lone pair, creating a negatively charged oxygen. After these initial steps, strong base is no longer required and hydrolysis must occur. The negatively charged nitrogen is protonated to regain its neutral charge, and the oxygen is protonated twice to harbor a positive charge in order to become a good leaving group. A lone pair from the nitrogen forms a pi-bond to expel the positively charged leaving group, and also causes the nitrogen to harbor a positive charge. The final step of the reaction is an elimination reaction (specifically an E2 reaction), which involves the extraction of the other hydrogen that was once benzylic, before the bicyclic compound was formed, whose electrons are converted into a new pi-bond in the ring system. This allows the pi-bond formed by nitrogen in the preceding step to be converted back into a lone pair on nitrogen to restore nitrogen's neutral charge.
Various techniques have been applied to increase the yield of the desired indole product. When the aromatic ring has electron-donating substituents higher yields are obtained, and the opposite is true when the aromatic ring has electron-withdrawing substituents. [1] However, when the R5 substituent is an electron-withdrawing substituent, the yield is increased instead of decreased. Additionally, the efficiency of the reaction is also heavily dependent on the bulkiness of the R6 substituent. The bulkier this group, the less efficient is the reaction. The conditions required for the Madelung synthesis are quite severe. Fortunately, the aforementioned modifications have been since applied to enhance its practicality, working to decrease the required temperature at which the reaction is performed and increase the desired product yield. For example, when electron-donating are placed on the aromatic ring of the N-phenylamide and an electron-withdrawing substituent is substituted at R5, the required temperature for the reaction decreases to approximately 25 °C. [1] Even more impressively, researchers have discovered that the required temperature for the Madelung synthesis decreases to a temperature range of −20 – 25 °C when butyl lithium (BuLi) and lithium diisopropylamide (LDA) bases are used, and when tetrahydrofuran is used as the solvent. [2] This particular modification, the use of either of these metal-mediated bases, is termed the Madelung-Houlihan variation. [3]
The Madelung synthesis has many important applications in chemistry, biochemistry, and industrial chemistry. This reaction served useful in synthesizing, with an 81% yield, the architecturally complex tremorgenic indole alkaloid (-)-penitrem D, a molecule naturally produced by ergot fungus that causes various muscular and neurological diseases in livestock. [4] Because this toxin ultimately causes significant economic problems in the livestock industry, understanding how to synthesize and easily decompose alkaloid (-)-penitrem D is of great importance. Nonetheless, the synthesis of such a complex molecule was, by itself, an incredible feat.
Another facet through which the Madelung synthesis has served useful is in the synthesis of 2,6-diphenyl-1,5-diaza-1,5-dihydro-s-indacene, from 2,5-dimethyl-1,4-phenylenediamine. [5]
This synthesis was performed without modification to the Madelung synthesis, using sodium ethoxide base at a temperature of 320 – 330 °C. This indacene has shown to be an organic light-emitting diode that may have important applications for low-cost light displays in commercial industry.
The Smith-modified Madelung synthesis, also called the Smith indole synthesis, was discovered in 1986 by Amos Smith and his research team. This synthesis employs a condensation reaction of organolithium reagents derived from 2-alkyl-N-trimethylsilyl anilines by esters or carboxylic acids to yield substituted indoles. [6] This synthesis has proven applicable to a wide variety of substituted anilines, including those with alkyl, methoxy, and halide groups, and can react with non-enolizable esters or lactones to yield N-lithioketamine intermediates. These intermediates then undergo intramolecular heteroatom Peterson olefination to yield indolinines, which then tautomerize to 2-substituted indoles. The Smith indole synthesis is one of the most important modifications to the Madelung synthesis.
The Smith indole synthesis begins by use of two equivalents of an organolithium reagent (as organolithium reagents are very strong bases) to extract a hydrogen from both the alkyl substituent and the nitrogen, resulting in a negative charge on both. The synthesis proceeds with a nucleophilic attack of the carbanion on the electrophilic carbonyl carbon of the ester or carboxylic acid. When this occurs, the pi-bond of the electrophile is converted into a lone pair on the oxygen. These lone pairs are then reconverted back into a pi-bond, resulting in the expulsion of the -OR group. Next, the negatively charged nitrogen performs a nucleophilic attack on the adjacent electrophilic carbonyl carbon, again causing the pi-bond of the electrophile to be converted into a lone pair on the oxygen. This negatively charged oxygen then performs a nucleophilic attack on the silicon atom of the trimethylsilyl (TMS) group, resulting in a tricyclic compound, and a positively charged silicon atom and neutral oxygen atom. The synthesis proceeds through an intramolecular heteroatom Peterson olefination, ultimately resulting in an elimination reaction which expels a TMSO group and forms a pi-bond in the five-membered ring at the nitrogen atom. Then, keto-enol tautomerism occurs, resulting in the desired product.
Aromatic compounds, also known as "mono- and polycyclic aromatic hydrocarbons", are organic compounds containing one or more aromatic rings. The word "aromatic" originates from the past grouping of molecules based on smell, before their general chemical properties were understood. The current definition of aromatic compounds does not have any relation with their smell.
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are Lewis bases.
In organic chemistry, a nucleophilic addition reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic additions differ from electrophilic additions in that the former reactions involve the group to which atoms are added accepting electron pairs, whereas the latter reactions involve the group donating electron pairs.
In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C−Li bond is highly ionic. Owing to the polar nature of the C−Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.
A substitution reaction is a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. Substitution reactions are of prime importance in organic chemistry. Substitution reactions in organic chemistry are classified either as electrophilic or nucleophilic depending upon the reagent involved, whether a reactive intermediate involved in the reaction is a carbocation, a carbanion or a free radical, and whether the substrate is aliphatic or aromatic. Detailed understanding of a reaction type helps to predict the product outcome in a reaction. It also is helpful for optimizing a reaction with regard to variables such as temperature and choice of solvent.
In electrophilic aromatic substitution reactions, existing substituent groups on the aromatic ring influence the overall reaction rate or have a directing effect on positional isomer of the products that are formed. An electron donating group (EDG) or electron releasing group is an atom or functional group that donates some of its electron density into a conjugated π system via resonance (mesomerism) or inductive effects —called +M or +I effects, respectively—thus making the π system more nucleophilic. As a result of these electronic effects, an aromatic ring to which such a group is attached is more likely to participate in electrophilic substitution reaction. EDGs are therefore often known as activating groups, though steric effects can interfere with the reaction.
In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds.
A nucleophilic aromatic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring. Aromatic rings are usually nucleophilic, but some aromatic compounds do undergo nucleophilic substitution. Just as normally nucleophilic alkenes can be made to undergo conjugate substitution if they carry electron-withdrawing substituents, so normally nucleophilic aromatic rings also become electrophilic if they have the right substituents.
The Bischler–Napieralski reaction is an intramolecular electrophilic aromatic substitution reaction that allows for the cyclization of β-arylethylamides or β-arylethylcarbamates. It was first discovered in 1893 by August Bischler and Bernard Napieralski, in affiliation with Basle Chemical Works and the University of Zurich. The reaction is most notably used in the synthesis of dihydroisoquinolines, which can be subsequently oxidized to isoquinolines.
Nucleophilic acyl substitution describes a class of substitution reactions involving nucleophiles and acyl compounds. In this type of reaction, a nucleophile – such as an alcohol, amine, or enolate – displaces the leaving group of an acyl derivative – such as an acid halide, anhydride, or ester. The resulting product is a carbonyl-containing compound in which the nucleophile has taken the place of the leaving group present in the original acyl derivative. Because acyl derivatives react with a wide variety of nucleophiles, and because the product can depend on the particular type of acyl derivative and nucleophile involved, nucleophilic acyl substitution reactions can be used to synthesize a variety of different products.
The Dakin oxidation is an organic redox reaction in which an ortho- or para-hydroxylated phenyl aldehyde or ketone reacts with hydrogen peroxide in base to form a benzenediol and a carboxylate. Overall, the carbonyl group is oxidised, whereas the H2O2 is reduced.
The Chichibabin reaction is a method for producing 2-aminopyridine derivatives by the reaction of pyridine with sodium amide. It was reported by Aleksei Chichibabin in 1914. The following is the overall form of the general reaction:
The Stieglitz rearrangement is a rearrangement reaction in organic chemistry which is named after the American chemist Julius Stieglitz (1867–1937) and was first investigated by him and Paul Nicholas Leech in 1913. It describes the 1,2-rearrangement of trityl amine derivatives to triaryl imines. It is comparable to a Beckmann rearrangement which also involves a substitution at a nitrogen atom through a carbon to nitrogen shift. As an example, triaryl hydroxylamines can undergo a Stieglitz rearrangement by dehydration and the shift of a phenyl group after activation with phosphorus pentachloride to yield the respective triaryl imine, a Schiff base.
Indole is an aromatic, heterocyclic, organic compound with the formula C8H7N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environment and can be produced by a variety of bacteria. As an intercellular signal molecule, indole regulates various aspects of bacterial physiology, including spore formation, plasmid stability, resistance to drugs, biofilm formation, and virulence. The amino acid tryptophan is an indole derivative and the precursor of the neurotransmitter serotonin.
Electrophilic amination is a chemical process involving the formation of a carbon–nitrogen bond through the reaction of a nucleophilic carbanion with an electrophilic source of nitrogen.
Benzylic activation and stereocontrol in tricarbonyl(arene)chromium complexes refers to the enhanced rates and stereoselectivities of reactions at the benzylic position of aromatic rings complexed to chromium(0) relative to uncomplexed arenes. Complexation of an aromatic ring to chromium stabilizes both anions and cations at the benzylic position and provides a steric blocking element for diastereoselective functionalization of the benzylic position. A large number of stereoselective methods for benzylic and homobenzylic functionalization have been developed based on this property.
Heteroatom-promoted lateral lithiation is the site-selective replacement of a benzylic hydrogen atom for lithium for the purpose of further functionalization. Heteroatom-containing substituents may direct metalation to the benzylic site closest to the heteroatom or increase the acidity of the ring carbons via an inductive effect.
Electrophilic aromatic substitution is an organic reaction in which an atom that is attached to an aromatic system is replaced by an electrophile. Some of the most important electrophilic aromatic substitutions are aromatic nitration, aromatic halogenation, aromatic sulfonation, and alkylation and acylation Friedel–Crafts reaction.
Secondary is a term used in organic chemistry to classify various types of compounds or reactive intermediates. An atom is considered secondary if it has two 'R' Groups attached to it. An 'R' group is a carbon containing group such as a methyl. A secondary compound is most often classified on an alpha carbon or a nitrogen. The word secondary comes from the root word 'second' which means two.
In organic chemistry, the hexadehydro-Diels–Alder (HDDA) reaction is an organic chemical reaction between a diyne and an alkyne to form a reactive benzyne species, via a [4+2] cycloaddition reaction. This benzyne intermediate then reacts with a suitable trapping agent to form a substituted aromatic product. This reaction is a derivative of the established Diels–Alder reaction and proceeds via a similar [4+2] cycloaddition mechanism. The HDDA reaction is particularly effective for forming heavily functionalized aromatic systems and multiple ring systems in one synthetic step.