Pyrido indoles, formation

General Procedure for Synthesis of 1,2,3,4-Tetrahydro-P-carboline by Domino Copper-Catalyzed Three-Component Indole Formation and Cyclization with t-BuOK Synthesis of 2-Methyl-l-propyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-hjindole (6a) and 2-Methyl-l-propyl-l,2,3,4-tetrahydropy-razino[l,2-a]indole (8a) (Table 1, Entry 11)... 

In a recent study, we showed that the more flexible pyrido[l,2-a]indole-based cyclopropyl quinone methide is not subject to the stereoelectronic effect.47 Scheme 7.17 shows an electrostatic potential map of the protonated cyclopropyl quinone methide with arrows indicating the two possible nucleophilic attack sites on the electron-deficient (blue-colored) cyclopropyl ring. The 13C label allows both nucleophile attack products, the pyrido[l,2-a]indole and azepino [l,2-a]indole, to be distinguished without isolation. The site of nucleophilic is under steric control with pyrido [1,2-a]indole ring formation favored by large nucleophiles. 

SCHEME 7.18 Formation and fate of the pyrrolo[l,2-a]indole (w — 0) and the pyrido[l,2-a] indole-based ( = 1) quinone methides. 

The formation of tetrahydro-jS-carbolines (l,2,3,4-tetrahydro-9//-pyrido[3,4-h]indoles) is well known (510R151), and many examples have been described. We have therefore chosen this plethora some recent transformations of Trp that allow some general conclusions about the stereochemistry of this transformation. 

One of the rare examples, where the palladium catalyzed closure of a six membered ring leads to an aromatic heterocycle is presented in 4.18. Intramolecular transformation of the 2-bromoindole derivative in the presence of a palladium-BINAP catalyst led to the formation of the a-carboline (pyrido[2,3- ]indole) skeleton. The ring closure was accompanied by the oxidation of the intermediate dihydrocarboline derivative.21... 

Formation of a cation radical of the diene may catalyze Diels-Alder reactions with certain dienophiles thus oxidation of substituted vinylindoles to the cation radical in the presence of a push-pull dienophile may form different heterocyclic compounds by the Diels-Alder reaction, for instance pyrido[l,2i7]indoles from vinylindoles and yS-enamino-esters [33]. Similarly, anodic oxidation in MeCN of certain oxazolidines in presence of vinyl ether leads to derivatives of oxazepines in a catalytic reaction in which the ring-opened radical cation of the oxazolidine adds to the vinyl ether and the radical cation of the resulting oxazepine oxidizes the oxazolidine [34]. 

Benzodihydropyrans and tetrahydroquinolines are obtained from reaction of 1,4-dienes with o-iodinated phenols and anilines, respectively. Formation of pyrido-[2,3-h]indoles from a-(o-bromoanilino)alkenenitriles is unusual, as Et N contributes [CHiCN] to form portion of the pyridine unit of the products. 

In his early 1970s outline of recent research on tobacco and tobacco smoke composition, Wakeham (4103) noted the reported presence of 9//-pyrido[3,4- ]indole (norharman) and l-methyl-9//-pyrido[3,4-fc]indole (harman) in cigarette smoke and discussed their possible formation by reaction of tryptophan and an aldehyde. As noted by Rodgman (3253a), the structure of the aldehyde reacting with tryptophan ultimately dictates the structure of alkylated norharmans found in CSC (see Table XVH.E-2). 

Ozonolyses of tetrahydro-lH-pyrido-[4,3-fe]-indoles resulted in the formation of a nine-membered keto-lactam, which could either be isolated or in situ cyclized to dihydropyrrolo[3,2-( ]quinolones, which can be derivatized by electrophilic aromatic substitution, selectively on the pyrrole moiety. In the ozonolysis reaction, alkyl cin-noline betaines were formed as side products, most likely via Cl side products. ... 

Methylthiazolidine-4-carboxylic acid, a condensation product of cysteine and acetaldehyde, occurs even in human blood as a consequence of ethanol consumption. Serine and threonine analogously produce C-2 substituted (2J S,4S)-oxazolidine-4-carboxylic acids (2-124). Heterocyclic products, C-2 substituted (2J S,4S)-pyrimidine-4-carboxylic acids, are also produced in the reaction of aldehydes with asparagine (2-125). Phenylalanine yields C-1 substituted (lJ S,3S)-tetrahydroisoquinoline-3-carboxylic acids (2-126) and analogous products arise from tyrosine. Tryptophan reacts with aldehydes under the formation of 9H-pyrido[3,4-b]indole (also known as -carboline or norharmane) derivatives, (lJ S,3S)-l,2,3,4-tetrahydro-fi-carboline-3-carboxylic acids (2-127, R = H or alkyl or residues of other aldehydes and sugars), the reaction of tryptamine yields the corresponding (lRS)-l,2,3,4-tetrahydro-P-carbolines. 

Finally, copper(II) catalysis was reported to be efficient in the formation of complex indolizine templates constructed Irom pyridine via a three-component reaction. When an excess of pyridine is reacted with equimolar amount of 1,4-naphthoquinone and dimethyl butynedioate (1 equiv) in the presence of copper(II) chloride under aerobic conditions, benzo[/]pyrido[l,2-a]indole-6,ll-dione is formed in 93% yield (eq 39). 

The carboline core is of high interest due to its presence in an array of compoimds, some of which are widely distributed in nature, including various plants, foodstuffs, marine creatures, insects, mammalians as well as human tissues and body fluids. Ghahremanzadeh et al. investigated the synthesis of a-carbolines, i.e., pyrido[2,3-b]indoles 169 (Scheme 94) in good yield via a four-component condensation reaction of indolin-2-one, 3-oxo-3-phenylpro-panenitrile, and various hydrazines and aldehydes in the presence of p-toluenesulfonic acid (p-TSA) at 140 °C in IL [BMlM][Br]. The reaction performed well with aromatic aldehydes, however, reaction with aliphatic aldehydes, for example, butanal or pentanal, complications such as incompletion of reaction, by-product formation, and difficulty in purifications arose, and the yield of the expected products were extremely poor. The authors claimed the methodology efficacious in terms of yield and product purity without p-TSA, only a trace of product was obtained even after 12 h. A similar reaction conducted in organic solvents afforded traces of tiie desired products [261]. 

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