Fischer indole synthesis
The Fischer indole synthesis is a classic organic reaction that constructs the indole heterocycle by cyclizing arylhydrazones—formed from phenylhydrazines and aldehydes or ketones—under acidic conditions and elevated temperatures, typically involving a [3,3]-sigmatropic rearrangement followed by dehydration.[1][2] Discovered in 1883 by Emil Fischer and Friedrich Jourdan, it remains a cornerstone method for synthesizing substituted indoles due to its versatility in accessing 2- and 3-substituted derivatives from enolizable carbonyl precursors.[3] This reaction's mechanism begins with the protonation of the hydrazone, facilitating the [3,3]-sigmatropic rearrangement to generate an enehydrazine intermediate, which then undergoes electrophilic aromatic substitution and rearomatization to yield the indole product; common catalysts include Brønsted acids like HCl or H₂SO₄ and Lewis acids such as ZnCl₂ or BF₃.[1][2] Early limitations, such as harsh conditions and regioselectivity issues with non-enolizable ketones, have been addressed through modern variants, including microwave-assisted processes, ionic liquid media, and metal-catalyzed improvements like Ru- or Pd-mediated hydrogen transfer, enabling milder reaction profiles and broader substrate scope.[3][2] The synthesis holds profound significance in natural product and pharmaceutical chemistry, as indoles form the core of many bioactive natural products, including alkaloids like strychnine, aspidospermine, and ellipticine, whose total syntheses frequently employ this method as a key step.[3] In medicinal applications, it facilitates the preparation of serotonin receptor agonists in the triptan class, such as sumatriptan, rizatriptan, eletriptan, and avitriptan, which are frontline treatments for migraines.[3] Its enduring utility underscores ongoing research into sustainable catalysts and green solvents to enhance efficiency and environmental compatibility.[3]History
Discovery
The Fischer indole synthesis was discovered in 1883 by Emil Fischer and Friedrich Jourdan during their studies on the reactions of phenylhydrazine derivatives with carbonyl compounds.[4] In their initial experiments, Fischer and Jourdan treated pyruvic acid with phenylhydrazine to form the corresponding hydrazone, which, upon heating in alcoholic hydrochloric acid, cyclized to yield an indole derivative—specifically, the reaction of N-methylphenylhydrazine with pyruvic acid produced 1-methyl-1H-indole-2-carboxylic acid, though the structure was not fully elucidated at the time.[4] This represented the first reported synthesis of an indole via such a process, stemming from efforts to prepare simple indole analogs.[5] Attempts to synthesize unsubstituted indole itself using phenylhydrazine and acetaldehyde under similar conditions were also explored around this period but initially unsuccessful in isolating the desired product. This breakthrough arose serendipitously from Fischer's broader investigations into hydrazines, which he had first synthesized in 1875 as versatile reagents for identifying and derivatizing carbonyl groups, particularly in carbohydrate structural analysis.[6] Motivated by the structural role of indoles in natural alkaloids, Fischer extended these methods to keto acids and aldehydes, leading to the unexpected cyclization observed.[7] The findings were detailed in their original publication in Berichte der deutschen chemischen Gesellschaft.[4]Early Developments
Following the initial discovery in 1883, Emil Fischer refined the indole synthesis in 1886 by employing anhydrous zinc chloride as a catalyst at approximately 200°C, which improved yields for key examples such as 2-methylindole (60%) and skatole (35%). These early optimizations highlighted the necessity of carbonyl compounds bearing alpha-hydrogens, such as certain aldehydes and ketones, to facilitate the reaction; non-enolizable carbonyls like those from formaldehyde or benzaldehyde generally failed to produce indoles efficiently. Contemporaries, including Walter Borsche, extended this scope in the early 1900s, notably through 1908 work with Witte and Bothe demonstrating dehydrogenation of 1,2,3,4-tetrahydrocarbazoles—formed via the synthesis—to yield carbazoles, thereby simplifying access to fused indole systems. In the 1920s and 1930s, explorations of alternative catalysts shifted toward mineral acids, with hydrochloric acid (HCl) in alcoholic media and sulfuric acid (H2SO4) proving effective for promoting cyclization under milder conditions than fused salts, often enhancing regioselectivity for 2- or 3-substituted indoles depending on the hydrazone substrate. These developments recognized persistent limitations, particularly low yields (often below 20%) with non-enolizable carbonyls due to insufficient enehydrazine formation, which were partially mitigated by varying solvents—such as introducing inert high-boiling options like methylnaphthalene to stabilize intermediates and reduce side reactions. A pivotal milestone came in the 1940s with isotopic labeling studies by Allen and Wilson, who used N¹⁵-enriched phenylhydrazones to confirm that the nitrogen atom from the hydrazone's terminal position is retained in the indole ring, while the proximal nitrogen is eliminated as ammonia, validating Fischer's proposed connectivity.[8]Reaction Overview
General Scheme
The Fischer indole synthesis is a classic method for constructing the indole core, involving the condensation of phenylhydrazine (\ce{C6H5NHNH2}) with an enolizable carbonyl compound, typically an aldehyde or ketone bearing an \alpha-methylene group (\ce{R-CO-CH2-R'}), to yield a substituted indole.[9] The general reaction can be represented as: \ce{C6H5NHNH2 + R-CO-CH2-R' ->[acid] 1H-indole (2-R, 3-R')} where the substituents R and R' determine the pattern of substitution at the 2- and 3-positions of the indole ring.[9] A key prerequisite for the carbonyl substrate is its ability to enolize, necessitating the presence of at least one \alpha-hydrogen on the carbon adjacent to the carbonyl group; non-enolizable carbonyls, such as benzophenone, do not undergo the reaction effectively.[9] The scope of the synthesis centers on forming the bicyclic indole framework, with the nitrogen atom derived from the phenylhydrazine occupying the 1-position and the carbonyl carbon and \alpha-carbon contributing to the 2- and 3-positions of the pyrrole ring, respectively.[9] Substituted phenylhydrazines allow for variation at the benzene ring of the indole (positions 4–7), while the choice of R and R' enables access to 2,3-disubstituted derivatives, including tryptophol precursors when R' = \ce{CH2CH2OH}.[9] The reaction typically proceeds under acidic conditions to facilitate the overall transformation, though specific catalysts are varied in practice. Regarding stereochemistry, the Fischer indole synthesis generally yields achiral or racemic indoles due to the planar aromatic nature of the product; asymmetric induction requires incorporation of chiral auxiliaries or catalysts in modified protocols.[9]Reagents and Conditions
The classical Fischer indole synthesis utilizes phenylhydrazine, typically employed as its hydrochloride salt for improved handling and solubility, and an enolizable carbonyl compound such as an aldehyde or ketone possessing at least one α-methylene group to enable the formation of the key ene-hydrazine intermediate.[5] A representative substrate is cyclohexanone, which reacts with phenylhydrazine to yield 1,2,3,4-tetrahydrocarbazole upon cyclization.[10] Catalysts are essential to promote phenylhydrazone formation, tautomerization, and subsequent rearrangement, with Brønsted acids including hydrochloric acid (HCl), sulfuric acid (H₂SO₄), polyphosphoric acid (PPA), p-toluenesulfonic acid (TsOH), and trifluoroacetic acid (TFA) being widely used; Lewis acids such as zinc chloride (ZnCl₂), zinc bromide (ZnBr₂), and boron trifluoride diethyl etherate (BF₃·OEt₂) also facilitate the process effectively.[11] Optimal temperatures range from 80°C to 150°C, depending on the catalyst and substrate, to balance reactivity and avoid side reactions like polymerization.[11] Reactions are often performed in protic solvents like ethanol, water, or acetic acid, which can also serve a dual role as mild catalysts, or under solvent-free conditions with stronger acids like PPA for enhanced efficiency.[11] Typical procedure involves refluxing the phenylhydrazine and carbonyl compound (1:1 molar ratio) in the chosen medium for 1–24 hours, followed by workup via cooling, filtration, and recrystallization; for instance, phenylhydrazine (1 mol) and cyclohexanone (1 mol) in acetic acid (6 mol equiv) at reflux (~118°C) for 2 hours provides 1,2,3,4-tetrahydrocarbazole in 76–85% yield after methanol crystallization.[10] Yields for simple cyclic ketones generally fall between 50% and 90%, influenced by substrate sterics and catalyst choice.[11] The method is limited to enolizable carbonyls, as non-enolizable ketones (e.g., benzophenone) or aldehydes lacking α-hydrogens fail to undergo the requisite tautomerization to the ene-hydrazine, halting the rearrangement step without modifications like preformed hydrazones or alternative catalysis.[5] Electron-donating substituents on the phenylhydrazine can promote premature N–N bond cleavage, leading to reaction failure instead of cyclization.[11] Safety protocols are critical due to phenylhydrazine's toxicity, mutagenicity, and suspected carcinogenicity, requiring use of gloves, fume hoods, and avoidance of skin contact or inhalation; additionally, concentrated acids demand protective eyewear and spill containment measures to mitigate corrosivity and exothermic risks during mixing.[12]Mechanism
Phenylhydrazone Formation
The phenylhydrazone formation constitutes the initial step of the Fischer indole synthesis, discovered by Emil Fischer and Friedrich Jourdan in 1883, wherein phenylhydrazine condenses with an aldehyde or ketone bearing an α-methylene group to produce the key hydrazone intermediate. This condensation occurs under mild acidic conditions, typically involving protic acids, and eliminates water to form the C=N bond characteristic of the hydrazone. The reaction can be represented by the following equation: \ce{C6H5NHNH2 + R-C(O)-CH2-R' ⇌ C6H5NH-N=CR-CH2-R' + H2O} Here, the acid catalyst plays a pivotal role by protonating the carbonyl oxygen, thereby increasing the electrophilicity of the carbon atom and promoting nucleophilic attack by the terminal amino group of phenylhydrazine. This activation facilitates the formation of a carbinolamine intermediate, followed by proton transfers and loss of water to yield the hydrazone. The resultant phenylhydrazone exhibits geometric isomerism, existing as E or Z configurations about the C=N bond, though these interconvert under reaction conditions. Crucially, the hydrazone tautomerizes to the ene-hydrazine isomer, positioning it for the ensuing sigmatropic rearrangement. Early mechanistic studies confirmed the hydrazone structure through spectroscopic techniques, with NMR revealing distinct imine proton signals (typically δ 7-8 ppm) for E/Z isomers and IR spectroscopy displaying the C=N stretching vibration at approximately 1600 cm⁻¹.Sigmatropic Rearrangement
Under acid catalysis, the initially formed phenylhydrazone tautomerizes to an ene-hydrazine intermediate, a crucial step that positions the system for the subsequent rearrangement. This isomerization involves protonation of the hydrazone nitrogen, followed by deprotonation at the alpha carbon of the carbonyl-derived moiety, generating a C=C double bond conjugated with the N-N single bond. The ene-hydrazine then undergoes a [3,3]-sigmatropic rearrangement, a pericyclic process that migrates the sigma bond between the nitrogens to form a new C-C bond between the ortho position of the aryl ring and the alpha carbon, yielding an o-aminophenyl imine. This transformation proceeds through a chair-like six-membered transition state, ensuring efficient orbital overlap and concerted bond breaking and forming.The rearrangement is suprafacial, occurring on the same face of the pi system, as predicted by the Woodward-Hoffmann rules for thermal [3,3]-sigmatropic shifts involving 6 pi electrons in a Hückel topology. This suprafacial stereochemistry leads to stereospecific outcomes in cases with substituents on the ene-hydrazine, where the configuration at the migrating centers is retained in the product. Acid plays a pivotal role by protonating the imine nitrogen of the ene-hydrazine, enhancing the electrophilicity of the C=N bond and lowering the activation barrier for the sigmatropic shift. Isotopic labeling studies using ^{15}N in the aryl-bound nitrogen of phenylhydrazine confirm that this nitrogen atom becomes the N1 position in the eventual indole ring, supporting the connectivity established during the rearrangement.[13] Note that while the pericyclic [3,3]-sigmatropic pathway is widely accepted, an alternative polar mechanism involving electrophilic aromatic substitution on a protonated ene-hydrazine has also been proposed under strongly acidic conditions.[3]Ar-NH-NH-CR=CH2 → [chair-like TS] → o-NH₂-C₆H₄-CR=NH (ene-hydrazine) (o-aminophenyl imine)Ar-NH-NH-CR=CH2 → [chair-like TS] → o-NH₂-C₆H₄-CR=NH (ene-hydrazine) (o-aminophenyl imine)