Indole compounds amination reactions

Topics reviewed during the year include the photochemistry of indoles, sulfoxides, pyrazoles and isothiazoles, (S-hetero)cyclic unsaturated carbonyl compounds, photoinduced single electron transfer (SET) reactions of amines and of azo compounds, SET reactions of organosilanes and organostannanes with Qo and ketones, photochromic polypeptides and di(hetero)arylethenes, processes in chromophore sequences on a-helical polypeptides,aryl-aryl coupling in furans, thiophenes and pyrroles," [3+2]cycloaddition of aromatic nitriles (and esters) with alkenes, and reactions of benzylsilane derivatives. ... 

The tricyclic system has also been constructed from an indole via electrophilic substitution reactions at positions 3 and/or 4. Synthesis of tricyclic ergoline synthons from 5-methoxy-lH-indole-4-carboxaldehyde has been described [45]. Sodium cyanoborohydride mediated reductive amination provided easy access to l,3,4,5-tetrahydrobenz[cd]indole-4-amines, compounds which show specificity for serotonin and dopamine receptors. 

Amines or amine extracts (1-5 mg) are treated with 500 jA of acetonitrile and 50 y of anhydride for 5 minutes at room temperature. These conditions are best, particularly with indole compounds, which are acid-sensitive [68]. More usually, a 1 1 mixture of acetonitrile and anhydride is used at 60 °C for up to 20 minutes, depen-ing on the substances to be derivatized. It may be possible to use lower temperatures and shorter reaction times the best thing is to work out optimal reaction conditions with pure compounds first [67, 70]. Excess solvent and anhydride are completely removed in vacuo, or the reaction mixture is blown dry with nitrogen, and the dried residue is dissolved in ethyl acetate (if required, the solvent may contain an injection standard) for analysis [71, 72]. Removal of excess reagent is essential before injection into a GC with an ECD, because if reagent gets into the detector it will saturate it for a long... 

Amines. Reaction of PCI3 with quaternary ammonium salts yields phosphaindolizines and thiazolodiazaphospholes. Imines produce phosphonates whereas hydrazones are converted to pyrazoles, indoles, and nitriles. Nitrones undergo rearrangement to secondary or tertiary amides and primary alkylnitro compounds are reduced to nitriles (eq 3). Diazonium salts are transformed to phosphonic acids. ... 

Similarly, indole itself could be converted by 2-methylsulfanyl-l,3-dithiolium iodide to its 3-dithiolium derivative, which gave 27 quantitatively with DBU. However, treatment of indoles, which bear the benzo-dithiolium moiety in the 2-position with tertiary amines, resulted in a black reaction mixture. All attempts to isolate the o-quinoid compound 28 failed (Scheme 7). 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

Vinyl- and acetylenic tricarbonyl compounds are reactive dienophilic components in Diels-Alder reactions. Cycloadditions of these compounds with substituted butadienes were recently used to develop a new synthetic approach to indole derivatives [14] (Scheme 2.9) by a three-step procedure including (i) condensation with primary amines, (ii) dehydration and (iii) DDQ oxidation. 

Phenols, secondary and tertiary aromatic amines, pyrroles, and indoles can be aminomethylated by treatment with formaldehyde and a secondary amine. Other aldehydes have sometimes been employed. Aminoalkylation is a special case of the Mannich reaction (16-15). When phenols and other activated aromatic compounds are treated withA-hydroxymethylchloroacetamide, amidomethylation takes place " ... 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

To make use of the Mannich reaction it is possible to methylate the N-atom of the new side chain and eliminate trimethylamine. The product, a 3-methyleneindoleninium salt, can then be trapped with suitable nucleophiles. In the example shown in Scheme 7.7b, cyanide ion is used, and reduction of the resultant nitrile yields the important amine trypta-mine. Indol-3-ylacetonitrile is also the source of indol-3-ylacetic acid and other biologically useful compounds (see Section 7.1.7). 

There is the raw stuff potentially available to answer this question. There are a couple of compounds known with the sulfur in the 4-position, which is the location of the oxygen atom in psilocybin. The 4-thio analogues have been synthesized from 4-methylthio-indole, via the oxalyl chloride method and reaction with the appropriate amine. With dimethylamine, the indoleglyoxylamide was made in a 43% yield and had a mp 163-164 °C. With diisopropylamine, the amide was made in a 27% yield and had a mp 190-192 °C. The final amines were prepared by the reduction of these amides with LAH in THF. N,N-Dimethyl-4-thiotryptamine (4-MeS-DMT) was obtained in a 68% yield and melted at 108-110 °C N,N-diisopropyl-4-methylthiotryptamine (4-MeS-DIPT) was obtained in a 61% yield and melted at 92-94 °C. In animal studies of behavioral disruption with these three compounds, there was systematic drop of potency in going from the 5-MeS-DMT to 4-MeS-DMT to 4-MeS-DIPT. 

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