One‐Pot Aminoethylation of Indoles/Pyrroles with Alkynes and Sulfonyl Azides

A general and efficient one‐pot aminoethylation of substituted indoles/pyrroles was accomplished for the synthesis of various tryptamine derivatives employing a combination of alkynes and sulfonyl azides as readily accessible aminoethylating agents. The reaction features a successful integration of copper‐catalyzed alkyne and azide cycloaddition to N‐sulfonyl‐1,2,3‐triazole, rhodium‐catalyzed selective insertion of α‐iminocarbenes onto the C3?H bond of indoles, and reduction of the resultant enamides to tryptamine derivatives employing either NaCNBH₃ or palladium catalyst, in one‐pot. The reaction also showed excellent functional‐group tolerance and allowed the synthesis of various substituted tryptamines in good to excellent yield. This transformation constitutes a one‐pot formal regioselective functionalization of terminal alkynes. Utility of the synthesized tryptamine was further demonstrated in the synthesis of dihydro‐β‐carboline and tryptoline.     

A mild and efficient route to 2-benzyl tryptamine derivatives via ring-opening of β-carbolines

We described a mild and easy method, in two steps, by which various benzyl groups were introduced in the C-2 position of tryptamine. The first step consisted on the synthesis of β-carbolines, starting from tryptamine derivatives, by a Pictet-Spengler reaction. Ring-opening of the β-carbolines, by hydrogenation, led to the desired 2-substituted benzyl tryptamine indole products. A supplementary step of alkylation could be realized to give N-alkyl-2-substituted benzyl tryptamine. During these reactions, nitrogen atoms require no step of protection.     

Synthesis Of 2-Acyltetrahydro-β-Carbolines By An Intramolecular α-Amidoalkylation Reaction

2-Acyltetrahydro-β-carbolines 7 have been obtained by cyclization of adducts 5 from imines 3 of tryptamine 1 and aldehydes 2 with acyl chlorides 4 as a result of an intramolecular a-amidoalkylation reaction in the presence of bases as N,N-dimethylaniline or Et₃N.     

Organocatalytic Enantioselective Pictet–Spengler Reaction of α-Ketoesters: Development and Application to the Total Synthesis of (+)-Alstratine A

We report herein an asymmetric Pictet–Spengler reaction of α-ketoesters. In the presence of a catalytic amount of simple alanine-derived squaramide and p-nitrobenzoic acid, reaction of tryptamines with methyl 2-oxoalkanoates afforded the corresponding 1-alkyl-1-methoxycarbonyl tetrahydro-β-carbolines (THBCs) in high yields and ee values. A primary kinetic isotope effect (KIE=4.5) using C2-deteurium-labelled tryptamine indicates that rearomatization through deprotonation of the pentahydro-β-carbolinium ion could be the rate- and enantioselectivity-determining step. A concise enantioselective total synthesis of (+)-alstratine A, a hexacyclic cagelike monoterpene indole alkaloid, featuring this reaction as a key step, was subsequently accomplished. Remeasurement of the [a]_D value of the natural product indicates that natural alstratine A is dextrorotatory rather than levorotatory as it was initially reported in the isolation paper.     

Water as an efficient medium for the synthesis of tetrahydro-β-carbolines via Pictet-Spengler reactions

A mild and efficient protocol for the Pictet-Spengler reaction in water using an acid catalyst has been described. The condensation of tryptophan, tryptamine, and N_b-benzyl tryptophan with different aldehydes having both electron-withdrawing and -donating substituents in the presence of a catalytic amount of TFA in water furnished tetrahydro-β-carbolines in good isolated yields. A salient feature of the water mediated Pictet-Spengler reaction was the general trend observed during the condensation of Trp-OMe and aryl/aliphatic aldehydes furnishing diastereomeric mixtures with a preference for the cis-isomer.     

A one-pot three-component reaction for the preparation of highly functionalized tryptamines

We have developed a general one-pot method to provide highly functionalized tryptamine derivatives, via a Fischer indole type pathway. In this article, we demonstrate optimal conditions for a one-pot indole synthesis, allowing for the synthesis of a broad scope of 2-methyl tryptamine derivatives and a precursor for the synthesis of the core structure of some akuammiline alkaloids. Additionally, further modification of the indole products is described.     

Characterisation of a proposed internet synthesis of N,N-dimethyltryptamine using liquid chromatography/electrospray ionisation tandem mass spectrometry

The psychoactive properties of N,N-dimethyltryptamine (DMT) are known to induce altered states of consciousness in humans. These properties attract great interest from clinical, neuroscientific, clandestine and forensic communities. The Breath of Hope Synthesis was reported on an internet website as a convenient two-step methodology for the preparation of DMT. The analytical characterisation of the first stage was the subject of previous publications by the authors and involved the thermal decarboxylation of tryptophan and the formation of tryptamine. The present study reports on the characterisation of the second step of this procedure which was based on the methylation of tryptamine. This employed methyl iodide and benzyltriethylammonium chloride/sodium hydroxide as a phase transfer catalyst. The reaction product was characterised by liquid chromatography/electrospray ionisation tandem mass spectrometry and orthogonal acceleration time-of-flight mass spectrometry. Quantitative evaluation was carried out in positive multiple reaction monitoring mode (MRM), which included synthesis of the identified reaction products. MRM screening of the product did not lead to the detection of DMT. Instead, 11.1% tryptamine starting material, 21.0% N,N,N-trimethyltryptammonium iodide (TMT) and 47.4% 1-N-methyl-TMT were detected. A 0.5% trace of the monomethylated N-methyltryptamine was also detected. This study demonstrated the impact on product purity of doubtful synthetic methodologies discussed on the internet.     

An Improved Synthesis of Canthin-6-one

Abstract

An improved route has been devised which provides canthin-6-one in the highest yield from tryptamine to date. Tryptamine is converted to N_b -benzyltryptamine via reaction with benzoylchloride and reduction using LAH. Pictet-Spengler condensation with 2-ketoglutaric acid, removal of the protecting group by CTH, and aromatization with MnO₂ affords canthin-6-one in 48% overall yield.     

Helicity Control in the Preparation of Chiral Co-crystals from Tryptamine and Achiral Carboxylic Acids by Pseudo-seeding

Abstract

Chiral crystals of tryptamine and achiral carboxylic acids such as p-chlorobenzoic acid, cinnamic acid, p-chlorocinnarnic acid and p-methylcinnamic acid were prepared by crystallization from the solutions of both components. All the crystals belonged to typical chiral space group P2₁2₁2₁. The crystal chirality is generated through the formation of a unidirectional twofold helix between the two components through quaternary ammonium salt interaction and hydrogen bonding in the lattice. This kind of spontaneous crystallization necessarily gives crystals of both clockwise and counterclockwise helicites. Here, pseudo-seeding based on utilizing these crystals as seed crystals was examined, resulting in successful helicity control in crystallization from solutions of tryptamine and different carboxylic acids.     

Diastereoselective synthesis of unsaturated 1,2-amino alcohols from α-hydroxy allyl ethers using chlorosulfonyl isocyanate

Diastereoselective synthesis of 1,2-amino alcohols was achieved from a highly diastereoselective allylic amination reaction of α-hydroxy allyl ethers using chlorosulfonyl isocyanate. Diastereoselectivities varied depending on the stereochemistry of the ethers used and the stability of the carbocation intermediate obtained during the reaction. We propose that this CSI reaction is the results of either a S_Ni or S_N1 mechanism, according to the stability of the carbocation intermediate.     

Sequential one-pot five-component synthesis of tetrazole-based spirotetrahydro-β-carbolines

A one-pot five-component two-step sequential synthesis of tetrazole-based tetrahydrospiro[indene-2,1′-pyrido[3,4-b]indole]-1,3-diones in moderate to good yields is described. The reaction consists of four-component condensation of aromatic aldehydes with tryptamine, trimethylsilyl azide (TMSN₃) and isocyanides, followed by addition of ninhydrin. These reactions presumably proceeded through Ugi-azide/Pictet–Spengler processes, respectively.     

Quantum dynamics of heavy light heavy reactions: Application to (F + CH4 → FCH3 + H) reaction

We apply the time-dependent theory to the collinear exchange reaction F + CH₄ → FCH₃ + H. We have performed detailed calculations on two-dimensional potential surfaces representing the ground electronic potentials of the collinear F + CH₄ → FCH₃ + H reaction, at incident energies. Transmission coefficients range from zero to unity, depending upon the incident energy. Normal modes of vibrations are displayed along the reaction path.     

A concise synthesis of indolic enamides: coscinamide A, coscinamide B, and igzamide

A concise synthesis of indolic enamides coscinamide A, coscinamide B, and the brominated tryptamine derivative igzamide is described. Both E- and Z-isomers of these natural compounds were obtained during the thermally assisted dehydration reaction and were tested for antitumor activity. Coscinamide B was found to possess antitumor activity against DU145 with an IC₅₀ of 7.6 μg/mL.     

Highly Enantioselective Tandem Michael Addition of Tryptamine‐Derived Oxindoles to Alkynones: Concise Synthesis of Strychnos Alkaloids

A highly enantioselective tandem Michael addition of tryptamine‐derived oxindoles to alkynones was developed by taking advantage of a chiral N,N′‐dioxide Sc(OTf)₃ catalyst. The reaction enables the facile preparation of enantioenriched spiro[pyrrolidine‐3,3′‐oxindole] compounds, which provides a novel strategy for the synthesis of monoterpenoid indole alkaloids. As a demonstration, the asymmetric synthesis of strychnos alkaloids [(?)‐tubifoline, (?)‐tubifolidine, (?)‐dehydrotubifoline] was achieved in 10–11 steps.     

Redox Amination Scope of Benzylic Ketones with Indoline: Synthetic and Mechanistic Insights

Bi(NO₃)₃·5H₂O‐Catalyzed redox amination scope and mechanistic insights of benzylic ketones with indoline are discussed. The experimental results demonstrate that the formation of N‐alkyl‐substituted indole/indoline derivatives over typically competitive redox and reductive amination processes is depending upon the reaction condition for the benzylic ketones.     

Reduction and N-Alkylation of α-Methylene-indolines with Sodium Cyanoborohydride in Carboxylic Acids

The reaction of α-methylene-indolines with NaCNBH₃ in carboxylic acids at room temperature can yield either 2β,3β-dihydro-indolines or their N-alkyl derivatives as main products with high selectivity, depending mainly on the carboxylic acid and on the reaction time when using a large excess of NaCNBH₃.     

A Facile Chemoenzymatic Approach: One‐Step Syntheses of Monoterpenoid Indole Alkaloids

Facile chemoenzymatic syntheses of cytotoxic monoterpenoid indole alkaloids with novel skeletons and multiple chiral centers are described. Synthesis of these alkaloids was achieved by a simple one‐step reaction using strictosidine and 12‐aza‐strictosidine as the key intermediates. Strictosidines were prepared by coupling of secologanin with tryptamine and 7‐aza‐tryptamine, respectively, using the immobilized recombinant Rauvolfia strictosidine synthase. A detailed stereochemical analysis is presented herein. The results provide an opportunity for a chemoenzymatic approach that leads to an increased diversification of complex alkaloids with improved structures and activities.     

Ultrasound-assisted synthesis of 3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-ones by novel core-shell bio-based nanocatalyst anchoring sulfonated L-histidine on magnetized silica (SO3H-L-His@SiO2-nano Fe3O4)

An efficient synthesis of 3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-ones is reported via a one-pot three-component reaction of 3-phenacylidenoxindoles, tryptamine, and dimedone under ultrasound irradiation using a newly prepared core-shell nanostructure. The utilized nanocatalyst is obtained by anchoring sulfonated L-histidine amino acid shell, as the bio part, on silica-nanomagnetite core (SO₃H-L-His@SiO₂-nano Fe₃O₄) and characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy (¹H NMR), field emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, thermogravimetric/differential thermal analysis, vibrating sample magnetometer measurements, transmission electron microscopy, and back-titration. The protocol contains several advantages, such as relatively short reaction times, simple work-up procedure by separation of the catalyst with an external magnet, the use of economical and environmentally friendly ultrasonic waves, and reusability and recoverability of the core-shell nano-promoter for three runs without significant activity loss.     

Palladium-catalyzed intramolecular α-arylation of aliphatic ketone, formyl, and nitro groups

Intramolecular arylation of properly designed substrates bearing a ketone, formyl, or nitro terminating group was achieved by use of a PdCl₂(Ph₃P)₂-Cs₂CO₃ reaction system to form a variety of carbocyclic compounds. Arylation in ketone compounds afforded benzene-annulated bridged or spirocycloalkanone derivatives, depending on the structure of the cyclization precursors. Arylation in formyl compounds occurred at the α-position (α-arylation) or at the carbonyl carbon (carbonyl-arylation) depending on the structure of the cyclization precursors and on the reaction solvent. An α-arylated secondary nitro group was partially transformed to ketone in the manner of the Nef reaction, whereas a tertiary nitro group was partially eliminated to afford a styrene-type olefin.     

PHOTOSENSITIZED REDUCTION OF PYRIMIDINE BASES BY TRYPTOPHAN*

Abstract— Thymine and uracil were chemically altered when irradiated with UV light in aqueous solution containing tryptophan as a photosensitizer. The reaction is inhibited by oxygen and is therefore not an example of photodynamic action. Unlike the pyrimidine bases, purine bases were not altered under similar reaction conditions. Two major photoproducts were identified. One of the products was identified as the reduced base, dihydrouracil or dihydrothymine. The quantum yield for formation of dihydrouracil was 0.24 times 10^--⁴ to 13.6 times 10^--⁴, depending upon the concentrations of uracil and the reaction temperature. Radical scavengers such as cysteine and nitrous oxide decreased the rate of dihydrouracil formation. Other indole compounds also sensitized the photoreduction of uracil, their quantum yields ranging from <1 × 10^--⁵ for tryptamine to 1.3 times 10^--³ for indole-3-acetic acid. A reaction mechanism is presented whereby the pyrimidines are reduced by electron transfer from a metastable charge transfer complex originating from the first excited singlet state of tryptophan.