Indole, 4,5,6,7-tetrahydro-, from

Pawelka and Stockigt (5S5) identified eight different indole alkaloids from cell suspension cultures of O. elliptica. The pattern of the alkaloids found was quite different from the above-mentioned results reported by Kuoadio and co-workers (779). The alkaloids identified were tetrahydroal-stonine, cathenamine, pleiocarpamine and two other methoxy-substituted heteroyohimbine alkaloids Corynanthe/heteroyohimbine type), norfluo-rocurarine Strychnos type), and apparicine and epchrosine Aspi-dosperma type). The last mentioned alkaloid was a new compound (729) not known from intact plants. 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

Many patents have been issued on the use of pyrogaUol derivatives as pharmaceuticals. PyrogaUol has been used extemaUy in the form of an ointment or a solution in the treatment of skin diseases, eg, psoriasis, ringworm, and lupus erythematosus. GaUamine triethiodide (16) is an important muscle relaxant in surgery it also is used in convulsive-shock therapy. Trimethoprim (2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine) is an antimicrobial and is a component of Bactrin and Septra. Trimetazidine (l(2,3,4-trimethoxybenzyl)piperazine (Vastarel, Yosimilon) is used as a coronary vasodilator. l,2,3,4-Tetrahydro-6-methoxy-l-(3,4,5-trimethoxyphenyl)-9JT-pyrido[3,4- ]indole hydrochloride is useful as a tranquilizer (52) (see Hypnotics, sedatives, ANTICONVULSANTS, AND ANXIOLYTICS). Substituted indanones made from pyrogaUol trimethyl ether depress the central nervous system (CNS) (53). Tyrosine-and glycine(2,3,4-trihydroxybenzyl)hydrazides are characterized by antidepressant and anti-Parkinson activity (54). 

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. ... 

Hi) Dehydrogenation. j3-Carboline derivatives may be obtained from tetrahydro-)3-carbohnes by zinc dust distillation or high temperatmre dehydrogenation with selenium or palladium black. Many of the complex indole alkaloids may be degraded, with bond cleavage, to yield simple )3-carbolines under these conditions and this approach has become a standard method in structural elucidations. Examples are numerous but outside the scope of this review. 

Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4//-pyrido-[l,2-u]pyrimidin-4-ones 289 by heating in 85% phosphoric acid, or in PPA yielded 7,12-dihydropyrimido[l, 2 l,2]pyrido[3,4-Z)]indol-4(6//)-ones 290 (96JHC799, 99MI12, 00MI22). From the 3-ester and 3-carboxylic acid derivatives 289 (R = COOEt, COOH) and decarboxylated products 290 (R = H) were obtained. 

A few intriguing developments in the area of tetrahydro-P-carboline synthetic methodology include the report of a catalytic asymmetric Pictet-Spengler reaction <06JACS1086> and an enantioselective Pd-catalyzed intramolecular allylic alkylation of indoles <06JACS1424>. A one-step synthesis of 1-substituted-P-carbolines from L-tryptophan has appeared that bypassed the tetrahydro intermediate <06T10900>. 

Yen and Chu subsequently also disclosed a related Pictet-Spengler reaction involving tryptophan and ketones for the preparation of 1,1-disubstituted indole alkaloids [417]. In the approach shown in Scheme 6.234, tryptophan was reacted with numerous ketones (12 equivalents) in toluene in the presence of 10 mol% of trifluoroacetic acid catalyst. Using microwave irradiation at 60 °C under open-vessel conditions, the desired products were obtained in high yields. Compared to transformations carried out at room temperature, reaction times were typically reduced from days to minutes. Subsequent treatment with isocyanates or isothiocyanates led to tetrahydro-/8-carbolinehydantoins. 

Nitrogen heterocycles undergo C-allylation in the presence of metalacyclic iridium-phosphoramidite catalysts. Recently, Yu and coworkers reported the C-allylation of indoles with the iridium catalyst derived from LI [86] and from phosphoramidites containing 2-methylindoline- and 2-methyl-l,2,3,4-tetrahydro-quinoline as the amino group (Table 4) [87]. No N-allylation was reported. However,... 

Azocino[4,5,6-cd]indoles 61 and 62 have been obtained from the corresponding Af-chloroacetyl derivatives of tryptamine and melatonine with the help of photocyclization. Further, lactam 62 has been reduced to 8-methoxy-3,4,6, 7-tetrahydro-lH,5H-azocino[4,5,6-cd]indole (63) under the action of B2Hg (69JMC(12)636 Scheme 19). 

This article deals with the chemistry of carbazoles, and except for their formation from carbazoles as illustrations of the chemistry of carbazoles, it specifically excludes that of 1,2,3,4-tetrahydro-, 1,2,3,4,4a,9a-hexahydro-, 1,2,3,4,5,6,7,8-octahydro carbazoles, etc., because from the viewpoint of chemical reactivity, these are indoles, anilines, pyrroles, and so on. This article also excludes carbazoles with additional fused aromatic or heteroaromatic rings, again except for the formation of such systems as illustrations of carbazole reactivity. The physical and spectroscopic properties are not covered. 

A number of reduction products of 2,8-dichloro-6,12-diphenyldibenzo[f>,/][l,5]diazocine (283) have been obtained (66JOC3356). LAH in ether gives mainly the frans-diphenyl-tetrahydro compound (282), whereas reduction in pyridine stops at the dihydro stage (284) (78%). Catalytic hydrogenation or zinc-acid reduction gives the tetracyclic indolo[3,2-6]indole system (286) which is readily oxidized back to the diazocine. Transannular cycliz-ation to (286) occurs on treatment of the dihydrodiazocine with NaH. Troeger s base derivatives, e.g. (287), were formed from the tetrahydro derivatives with formaldehyde. 

A second type of route from pyrroles to indoles involves construction of a vinylpyrrole suitable for [4 + 2] cycloaddition leading to a dihydro- or tetrahydro-indole (Scheme 19) (80JOC4515, 81T1597). The dihydro systems can be easily aromatized. 2-Nitrovinylpyrroles, which are readily available by condensation of pyrrole-2-carbaldehyde with nitromethane, give fully aromatic indoles on reaction with dienophiles (equation 139) (73JCS(P1)2450). The aromatization results from elimination of nitrous acid and a further dehydrogenation. 

A 7-substituted 3,4,6,7-tetrahydro-2//-pyrido[2,l-h][l,3]oxazine was formed as by-product the alkylation of methyl 2-(benzyloxycarbonyl-6-oxo-l-phenylsulfonyl)indol-2-yl)-2-azabicyclo[2,2,2]octane-6-enrfo-car-boxylate with 3-iodopropanol from a 3-substituted l-(3-hydroxypropyl)-2,3-dihydropyridinium intermediate (90JOC6028). 

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