Reactions of the Carbolines

Reactions of the Fully Aromatic Carbolines i. Substitutions at Carbon 

Relatively little is known concerning the substitution reactions of the carbolines. The most studied reaction is that of nitration. Nitration of l-methyl-j8-carboline gave two mononitro derivatives. The highermelting isomer, which was formed predominantly (57% yield), was shown to be 6-nitro-l-methyl-j8-carboline (253 R = CH3) by its conversion into 6-bromo-l-methyl-j5-carboline the latter was synthesized unambiguously from 5-bromotryptophan and acetaldehyde. The lower melting isomer, recovered in 20% yield, was presumed to be the 8-nitro derivative (254), although this was not established. Nitration of j8-carboline with concentrated nitric acid at 35° has been reported to yield 6-nitro-j3-carboline (253 R = H) as the sole product. Only the 6-nitro derivatives (255) were isolated on nitration 

Spot Tests, Organic Applications. Vol. II, p. 296. Elsevier, Amsterdam, 1954. 

Nitration of quinindoline gave the expected 9-nitro derivative (261). A single mononitro compound was formed from the 3,4-dihydro-jS-carboline, harmaline this was 6-nitroharmaline, since on oxidation it yielded 3-nitro-4-methoxybenzoic acid. 

The bromination of 7-methoxy-l-methyl-j8-carboline (harmine) was studied by Fischer. He obtained a compound, Ci3Hi2Br4N20, which he called tetrabromoharmine, by the action of bromine water on a dilute sulfuric acid solution of harmine. The bromination of harmine was reinvestigated by Hasenfratz, who found that two products (both hydrobromides) could be isolated when harmine was treated with bromine in aqueous acetic acid. The major component formed colorless needles and was called bromoharmine hydrobromide (free base colorless needles, m.p. 275°), while the product obtained in lesser amount was a canary-yellow dihydrate which was named isobromoharmine hydrobromide (free base colorless needles, m.p. 

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The intense blue color which is obtained when tryptophan, in the presence of an aldehyde, is treated with concentrated sulfuric acid containing an oxidizing agent (Adamkiewicz-Hopkins-Cole reaction) was beheved to involve formation of a tetrahydro-j8-carboline intermediate, since most l,2,3,4-tetrahydro-j8-carbohne derivatives yield a similar color with concentrated sulfuric acid containing an oxidizing agent. The two colors have now been shown to have different absorption spectra. The nature of the carboline-blue color is still obscure. 

Reaction of j8-carboline derivatives with hydrogen peroxide or perbenzoic acid and of S-carboline with peracetic acid yields the corresponding yr-A-oxide (e.g. 280). 

The pyrrolo[3, 4 2,3]azepino[4,5,6-cd] indole-8,10-dione system can be accessed by reaction, under conditions used for the Pictet-Spengler reaction, of the imines from condensation of 3-amino-4-(3-indolyl) pyrrolin-2,5-diones with aldehydes or ketones. Cyclisation to the pyrrolo-P-carbolines did not occur under the conditions <00JHC1177>. 

A more promising approach to a synthesis of vinblastine-type compounds can be derived from the significant observation that reaction of one enantiomer of the carboline ester (-l- )-38 with p-nitrobenzyl chloro-formate and 3-methoxy-A/, A-dimethylaniline, at 25°C, gave a model (-t-)-congener of 39 in 72% yield and 55% enantiomeric excess, thus indicating a conformational retention in the nine-membered cationic intermediate formed on acylation of the carboline ester 38 (37b). 

Dodd and co-workers (5) reported the first known synthesis of 11//-indolizino[8,7-h]indoles by the cycloaddition reaction of a nonstabilized ylide 21 and diethylacetylene dicarboxylate (DEAD). The azomethine ylide, formed by the alkylation of the 3,4-dihydro-p-carboline (22) with trimethylsilyl methyl triflate to the triflate salt, followed by in situ desilyation with cesium fluoride, underwent cycloaddition with DEAD at low temperature. The expected major cycloadduct 23 was isolated, along with quantities of a minor product 24, presumed to have been formed by initial reaction of the ylide with 1 equiv of DEAD and the intermediate undergoing reaction with a further equivalent of DEAD before cyclization. Dodd offers no explanation for the unexpected position of the double bond in the newly generated five-membered ring, although it is most likely due to post-reaction isomerization to the thermodynamically more stable p-amino acrylate system (Scheme 3.5). 

Aminomethylene pyrrolidones are converted in a similar manner to / -carbolines by reaction with a substituted phenylhydrazine (equation 161). The reaction involves hydrazinolysis of the enaminone followed by the Fischer reaction of the intermediate spiro-compounds230. 

The importance of indoloquinolizidine alkaloids has stimulated the development of synthetic methods. For example, reaction of the compound 492 with tryptamine 493 gives the enaminone 494. Treatment of 494 with hydrogen chloride gives the )8-carboline salt 495, which is neutralized and reduced to the indoloquinolizidine 496, Scheme 133 (82TL3301). 

Napieralski reaction of the amide 54, was subjected to catalytic hydrogenation over Pt02 in ethanol to afford the 1,3-cm disubstituted tetrahydro- -carboline 55. TVb-Alkylation, respectively with l-bromo-4-acetoxy-2(Z)-butene or l-bromo-2( )-butene in CH3CN in the presence of NaHCOa, gave the tertiary amines 56 or 57. After protection of the Na function in 56 and 57 with an acetal group, Dieckmann cyclization was conducted with... 

In 1992, Molina et al. synthesized partial structures of lavendamycin using the aza-Wittig reaction as the main strategy (68) to form a /3-carboline at the 2-position of a quinoline (Scheme 23) (68). The reactions of the iminophosphorane 194, prepared from 3-formyl-l-methyl indole by treatment with ethyl azidoacetate and triphenylphosphine, with the 2-formyl-quinoline derivatives 195 in toluene at 160°C in a sealed tube gave the corresponding quinoline derivatives 196 and 197. Treatment of iminophosphorane 194 with pyruvaldehyde yielded the key j3-carboline intermediate 198, which was reacted alternatively with the 2-aminobenzaldehyde 199 and JV-(0-formylphenyl)triphenyliminophosphorane 200 to obtain the corresponding partial structures of lavendamycin, 201 and 202, respectively. 

Arylation with various heterocyclic compounds can be carried out when their reactive halides are available at proper positions. For example, the antihistamine norastemizole derivative 85 was synthesized by the reaction of the chlorobenzim-idazole 83 with the diamine 84. Selective arylation of the primary amine in the diamine 84 proceeded with high selectivity [58]. BINAP is a good ligand for the amination of 3-bromopyridine (86) [59]. Similarly benzylamine was introduced to the bromopyridine moiety of the 3-carboxy- -carbolines 87 to give 88 [60]. Another example is the C-8 aminated adenosine derivative 90 was obtained in a high yield by the amination of 89 [61]. 

The 4-pyridone (151), an analogue of maltol, has been isolated from the reaction of lactose or maltose with a hot aqueous solution of methylammonium acetate. The heterocyclic derivative (152) and the 1,2,4-triazine derivatives (153) have been obtained from 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide by standard routes. Bischler-Napieralski cyclization of the corresponding iV-acetyl-tryptamines and dehydrogenation (Pd-BaSO ) gave the )S-D-glucopyranosyl-carboline (154) and the related a-L-arabinopyranosylcarboline. The spin-labelled nitroxide derivative (155) has been prepared by reaction of the nicotinamide derivative with 2,3,5-tri-0-benzoyl-j8-D-ribofuranosyl bromide. ... 

Yet another example of a jS-carboline elaboration of the yohimbine skeleton is found in the work of Danishefsky (Scheme 3.72) (120). Diels-Alder reaction of jS-carbolines 255 or 415 with the readily prepared diene 416 afforded pentacyclic lactams 417 or 418, respectively. Amide reduction of 417 followed by enol ether hydrolysis afforded known yohimbane ketone 419 (114, 121). Attempts to isomerize the 7i-bond in 419 to give the a,j8-unsatu-rated ketone 401 were unsuccessful. Nevertheless, this chemistry demonstrates how Diels-Alder reactions of jS-carboline derivatives can be used to construct the pentacyclic skeleton of the yohimbines in an eflScient fashion. 

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). 

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