6 Carbolines

An efficient methodology for the synthesis of 5-carbolines 28 was developed by Cao, Lai, and coworkers. Such methodology is based on a Pd-catalyzed cascade reaction between 2-iodoanilines and N-tosyl-enynamines (2012 OL38). 

---

A special application of the Japp-Klingemann/Eischer sequence is in the preparation of tryptamines from piperidone-3-carboxylate salts, a method which was originally developed by Abramovitch and Shapiro[2]. When the piperidone is subjected to Japp-Klingemann coupling under mildly alkaline conditions decarboxylation occurs and a 3-hydrazonopiperidin-2-one is isolated. Fischer cyclization then gives 1-oxotetrahydro-p-carbolines which can be hydrolysed and decarboxylated to afford the desired tryptamine. 

The synthesis of triethoxysilane (28) and trimethoxysilane (29) has also been achieved by direct process. In 1980 there were no direct processes for the production of alkoxysilanes. In 1995 Silbond in Weston, Michigan, and Carboline in St. Louis, Missouri, operated processes for the production of tetraethoxysilane in the United States, and OSi/Witco announced start-up of a process to produce triethoxysilane and tetraethoxysilane in TermoH, Italy. 

Perhaps the most important application of the Mannich reaction is in the synthesis of 3-dialkylaminoindoles. Intramolecular versions of this reaction are also possible, as illustrated by the formation of the /S-carboline (73). 

Protoporphyrin-IX, N-methyl-, 4, 396 Protoporphyrins, 4, 382 photooxygenation, 4, 402 Prototropic tautomerism polyheteroatom six-membered rings, 3, 1055 Prozapine properties, 7, 545 Pschorr reaction carbolines from, 4, 523 dibenzazepines from, 7, 533 dibenzothiophenes from, 4, 107 phenanthridines from, 2, 433 Pseudilin, pentabromo-synthesis, 1, 449 Pseudoazulene synthesis, 4, 526 Pseudobases in synthesis reviews, 1, 62 Pseudocyanines, 2, 331 Pseudothiohydantoin synthesis, 6, 296 Pseudouracil structure, 3, 68 Pseudoyangonin IR spectra, 3, 596 Pseudoyohimbine synthesis, 2, 271 Psicofuranine biological activity, 5, 603 as pharmaceutical, 1, 153, 160... 

Bisehler-Napieralski reaetions, 4, 279 carboline synthesis from, 4, 516 Mannieh-type reactions, 4, 279 sulfur isosteres, biological activity, 4, 913 synthesis, 4, 337, 913 Tryptophan... 

Barger el al. took the view that the alkaloid contains two tryptamine residues, one represented in the degradation products by -methyltrypt-amine, and the other by methyl-3-carboline, and on this basis proposed formula (II). Manske and Marion, on the contrary, regard 2V-methyl-tryptamine and 3-carboline as originating from the same moiety of the molecule, the other half being represented by 4-methylquinoline, and on this conception based formula (III). 

Apart from the syntheses already quoted as of possible biological interest, mention must be made of a series which are primarily of chemical interest. Kermack, Perkin and Rob mson prepared norharman, i.e., /S-carboline (VII) by warming A-methylindole-2-carboxyacetalylamide (XVIII) with alcoholic hydrogen chloride, thereby converting it into 2-keto-l-methyl-2 3-dihydro-/S-carboline (XIX), which on distillation... 

These formulae explain the scission products of the two alkaloids and the conversion of evodiamine into rutaecarpine, and were accepted by Asahina. A partial synthesis of rutaecarpine was effected by Asahina, Irie and Ohta, who prepared the o-nitrobenzoyl derivative of 3-)3-amino-ethylindole-2-carboxylic acid, and reduced this to the corresponding amine (partial formula I), which on warming with phosphorus oxychloride in carbon tetrachloride solution furnished rutaecarpine. This synthesis was completed in 1928 by the same authors by the preparation of 3-)S-amino-ethylindole-2-carboxylic acid by the action of alcoholic potassium hydroxide on 2-keto-2 3 4 5-tetrahydro-3-carboline. An equally simple synthesis was effected almost simultaneously by Asahina, Manske and Robinson, who condensed methyl anthranilate with 2-keto-2 3 4 5-tetrahydro-3-carboline (for notation, see p. 492) by the use of phosphorus trichloride (see partial formulae II). Ohta has also synthesised rutaecarpine by heating a mixture of 2-keto-2 3 4 5-tetrahydrocarboline with isatoic anhydride at 195° for 20 minutes. 

In a recent paper, Schopf and Steuer ° describe the synthesis under physiological conditions of rutaecarpine from 4 5-dihydro-3-carboline perchlorate and a-aminobenzaldehyde. 

Leonard and Elderfield have also carried out degradation experiments with alstonine and its tetrahydride. On fusion with potassium hydroxide at 300-350° in nitrogen, alstonine furnishes barman (p. 490) and indefinite basic and acidic fractions. Tetrahydroalstonine on like treatment produces barman, worharman, and three unidentified bases, each of which fluoresces blue in alcoholic hydrochloric acid Base A, C4,H4gN2, m.p. 171-5 to 172-5°, forms a picrate, m.p. > 267° is probably a substituted -carboline. Base B, or 18 3, gives apicrate, m.p. 261° (dec.). Base C,... 

On thermal decomposition of alstonine at 300-330°, the bases produced distilled at l20-170°/0-15 mm., and on fractionation as picrates gave three products Base D, C4,HigN2, picrate, m.p. 254-6°. Base E, C18H20N2, or CjgHgaNj, picrate m.p. 193-5-195°, not identical with Sharp s alstyrine, and base F, Cj3Hi2N2, m.p. 79-81°, pierate, m.p. 261-262-5°, hydrochloride, m.p. about 275° (dec.), methiodide, m.p. 283-4° (dec.). Base F has an ultraviolet absorption spectrum very similar to that of 2-ethyl- -carboline, but it is not that substance nor is it 1 2-dimethyl-/3-carboline, 2 3-dimethyl-j3-carboline, 1-ethyl- -carboline or 3-ethyl- -wocarboline. Base F was also produced when alstonine was distilled with zinc dust. 

Tetrahydroalstonine gives with the Adamkiewicz test, as modified by Harvey et al., a colour similar to that given by yohimbine, which is taken to indicate the presence of a tetrahydro-/3-carboline ring system. Further, the ultra-violet absorption curves for yohimbine and tetrahydroalstonine... 

The Graebe-Ullman carbazole synthesis has been enmloyed in the preparation of substituted carbolines, as well as indolo[2,3-i] quinolines, which are often difficult to synthesize via other approaches, for example, the Fischer indole process. 

One can also use diethyl phosphorocyanidate (DEPC) to effect a similar transformation. This was the reagent of choice in the generation of l-substituted-4-oxygenated-P-carbolines (49— 50). 

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

Bischler-Napieralski reactions of N-acyl tryptamine derivatives 16 are believed to proceed via a related mechanism involving the initial formation of intermediate spiroindolenines (17) that rearrange to the observed 2-carboline products (18). The presence of these intermediates has been inferred by the observation of dimerized products that are presumably formed by the intermolecular trapping of the spiroindolenine by unreacted indole present in the reaction mixture." ... 

This reaction is also a key method for the formation of tetrahydro-P-carbolines 5 from indole bases 4 and aldehydes, ketones, or 1,2-di carbonyl compounds 2. These reactions are similarly acid-catalyzed or thermally-induced and have been utilized in the synthesis of numerous indole alkaloids. 

A few years later, Tatsui developed this process for use with indole bases and prepared l-methyl-l,2,3,4-tetrahydro-P-carboline 11 from tryptamine 9 and acetaldehyde 10 under acid catalysis. ... 

The Pictet-Spengler condensation of indole bases and carbonyl compounds to form 3-carbolines involves a slightly different mechanism than the isoquinoline... 

Several factors influence the diastereoselectivity of the Pictet-Spengler condensation to form 1,3-disubstituted and 1,2,3-trisubstituted tetrahydro-P-carbolines (39 and 40, respectively). The presence or absence of an alkyl substituent on the nitrogen of tryptophan has a large influence on the relative stereochemistry of the tetrahydro-P-carboline products formed from a condensation reaction with an aldehyde under various reaction conditions. 

---