2-Oxindoles, 1-methoxy

Another version of the o-aminobenzyl anion synthon is obtained by dilithi-ation of A-f-Boc-protected o-alkylanilines. These intermediates are C-acylated by DMF or A"-methoxy-At-melhyl carboxamides, leading to either 3- or 2,3-disubstituted indoles. In this procedure dehydration is not spontaneous but occurs on brief exposure of the cyelization product to acid[4]. Use of CO as the electrophile generates oxindoles. 

The Gassman indole synthesis has one serious limitation. Attempts to use anilines with an ortho/para- methoxy moiety failed to indolize. One means to overcome this was synthesis of the corresponding oxindoles followed by reduction to the indoles. ... 

Many early claims of having prepared simple 1-hydroxyindoles have proved to be unfounded, although the unusually stable l-hydroxy-2-phenylindole was obtained in 1895.1-Hydroxyindole itself polymerizes on attempted isolation, while O-acylation, O-alkylation, or the presence of substituents greatly stabilizes the molecule. One 1-hydroxyindole antibiotic has been identified and is the only 1-hydroxyindole derivative isolated from natural sources so far. In contrast, a substantial number of 1-methoxyindoles occurs in various plants, and some of these may inhibit tumor formation in mammals. The biochemistry of these compounds, which include 1-methoxy-indoles, -indolines and -2-oxindoles, has not been widely investigated and could be a very fruitful area for new research which might well lead to novel medicinal agents and other useful compounds. 

The 3-methylene group of l-methoxy-2-oxindole (163) is easily ionized to give a carbanion that undergoes well-known types of reactions with alkyl halides or activated olefins without loss of the methoxyl group (e.g. 

About a dozen l-methoxy-2-oxindole alkaloids have been isolated and identified, either by X-ray crystallography or by sophisticated spectroscopy. Most are associated with their des-l-methoxy analogues in the plants. Very little chemistry involving the l-methoxy-2-oxindole ring system of these compounds has been done, and they will therefore be considered only briefly. 

Gelsemicine (234) was the first naturally occuring l-methoxy-2-oxindole to be discovered in Gelsemium sempervirens roots (65MI3). Its structure... 

The lithium aluminum hydride reduction of l-acetyloxy-2-oxindole (287) gave a polymer, but that of the 1-methoxy analogue (288) yielded [78JCS(P1)1117] 1-methoxyindole. Application of this method (83H1797) led to a valuable synthesis of lespedamine 291. Alkylation of 288 by 1,2-dibromoethane and sodium hydride gave a 3,3-spiro derivative, which dimethylamine converted to 289. Reduction with lithium aluminum hydride now gave 290, as a mixture of isomers, which was dehydrated instantly by acid to 291 (see Section 1II,E). 

A unique oxindole synthesis is the addition of diphenylketene to the mono-A-phenylimine of benzoquinone the resulting spiro-P-lactam (18) rearranges to give a 62% overall yield of 5-hydroxy-l,3,3-triphenyloxindole (19), which can be methylated to the 5-methoxy compound,35 which in turn could be converted to the Fischer s base. 

The UV-spectrum of mitragynine differs notably from the spectra of the other Mitragyna alkaloids. Whereas the absorption of the latter indicate the presence of oxindole nuclei, the spectrum of mitragynine shows a greater resemblance to that of the ajmalicine group of alkaloids (5). The presence of an indole nucleus is also suspected from its color reactions (2) and confirmed by the isolation of indole derivatives (so far unidentified) and 5-methoxy-9-methylharman (I) from the products of zinc dust distillation (6). The identification by synthesis (51) of this degradation product is of some interest, since the alkaloid itself does not apparently contain an iV-methyl group. Moreover, this was the first demonstration of the occurrence of a 4-hydroxyindole derivative in nature. 

Cyclization of the anilide 213 using TiCU produced the 3-chloro-substituted oxindole 214 (Equation 69), whereas a similar reaction induced by BF3-OEt2 gave the corresponding methoxy-substituted derivative <1998T4889>. Lewis acids have also been used in an approach to indole-2-carboxylates based on cyclization of (Z)-A(A -dimethyl-aminopropenoates derived by exposure of A -arylglycinates to DMEDMA <2006SL749>. 

The intramolecular version of this aromatic substitution provides a route to nitrogen heterocycles, in particular l-methoxy-2-oxindoles. 

A new simple oxindole alkaloid, (-)-horsfiline (57) was obtained from Horsfieldia superba (Myristicaceae), in addition to the known alkaloids 6-methoxy-2-methyl-l,2,3,4-tetrahydro-P-carboline (58) and 5-methoxy-A, -dimethyltryptamine [59]. Horsfiline is a simple spiro-pyrrolidinyloxindole, its structure was deduced from spectral data (MS NMR) as well as by partial synthesis from 58 via oxidation with Pb(OAc)4 to the acetoxyindolenine 59, followed by acid catalysed rearrangement (MeOH/AcOH) to ( )-horsfiline (Scheme 2) [59]. 

Monoterpene Bases.—Yohimbine-Corynantheine (and Related Oxindoles)-Pier aline Group. It is well known that 3,4-dehydroyohimbane (35a) is reduced by zinc-acetic acid to a mixture of yohimbane (35c) and i/ -yohimbane (35d) however, when 10-methoxy-3,4-dehydroyohimbane (35b) was similarly treated, a 2,3,4,7-tetrahydro-derivative (17 % yield) was formed as well as the corresponding 10-methoxy-yohimbanes. It was shown that this did not arise by further reduction of either of the methoxy-yohimbanes and no explanation is yet available for this interesting difference. Reserpine, a 6-methoxyindole, underwent C(3)-N(4) bond fission on reaction with zinc-acetic acid, as did indoles with no ring A methoxy-group. Cleavage of the C(3)-N(4) bond with the formation of N(4)-cyano-C(3)-alkoxy- or hydroxy-seco-derivatives was observed when yohimbine, i/ -yohimbine, and methyl reserpate were subjected to von Braun degradation conditions in alcohol or aqueous solution. 

Herbavine is a heteroyohimbine oxindole with two aromatic methoxy-groups.25... 

The skeletal structure of oxindoles of the secoyohimbane type, typified by rhynchophylline and isorhynchophylline, rests on a mass of chemical and physical evidence which has been discussed in earlier volumes. Some physical properties of members of this group are presented in Table II. The UV spectra of all the oxindole alkaloids are closely related (Table III) and are satisfactorily explained on the basis of contributions of an oxindole and a -methoxy acrylic ester... 

Oxidation of rauvanine, a 9-methoxy indole alkaloid of known 19 8-methyl normal conhguration, with <-butyl hypochlorite gives rise to two oxindoles designated as rauvanine oxindole A (64 mp 234-236°) and B (65 mp 210-212°) which must belong to the normal series (57). The relatively shielded position of the C-19 proton of both oxindoles, when compared with the mitraphyllines, is in agreement with their formulation as 19j8-methyl normal oxindoles. 

---