Methoxy-substituted indoles

Cook and colleagues improved Mori-Ban reaction and developed the general approach to the total synthesis of 9-methoxy-substituted indole alkaloids/ The intermediate 57 was successfully synthesized via the modified method and provided a key material 58 for preparations of mitragynine, as well as 9-methoxygeissoschizol and 9-methoxy- b-methylgeissoschizol. 

Asymmetric synthesis of vindoline has been conducted similarly. As is the case with 533 (Scheme 16.114), the substrate 541 (Scheme 16.116) with the dienophile of E-configuration provides higher yield than the analog with the Z-configuration of the dienophile. An important difference between these two substrates is that methoxy-substituted indole initiates the [4 + 2] cycloaddition to a minor extent, which lowers the overall yield to 51 % compared to 72% for the unsubstituted indole. Apparently, the more electron-rich indole competes for the diene more effectively in the... 

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

The pivotal step in this sequence is an electrophilic substitution on indole. Although the use of l,3-dithian-2-yl carbanions is well documented, it has been shown only recently that 1,3-dithian-2-yl carbenium ions can be used in a Priedel-Crafts type reaction. This was accomplished initially using 2-methoxy-l,3-dithiane [1,3-Dithiane, 2-methoxy-] or 2-metlioxy-l,3-dithiolane [1,3-Dithiolane, 2-methoxy-] and titanium tetrachloride [Titanate(l —), tetrachloro-] as the Lewis acid catalyst.9 2-Substituted lysergic acid derivatives and 3-substituted indoles have been prepared under these conditions, but the method is limited in scope by the difficulties of preparing substituted 2-methoxy-1,3-dithianes. l,3-Dithian-2-yl carbenium ions have also been prepared by protonation of ketene dithioacetals with trifluoroacetic acid,10 but this reaction cannot be used to introduce 1,3-dithiane moieties into indole. 

The fluorination of 1-substituted indole 32 with F-Teda BF4 (6) in acetonitrile or acetonitrile/ methanol gives 3-fluoro-2-methoxy-l-tosyl-2,3-dihydroindole (33) in 48% isolated yield.87 Relative stereochemistry about the 2,3-bond in the dihydropyrrole ring was confirmed as trans by X-ray crystallographic analysis. F-Teda BF4 (6) reacts with 2- and 3-trimethylstannyl-sub-stituted 1-tosylindoles to give the corresponding fluoroindoles in 40 and 21 % yield, respectively.108... 

The extension of the use of lactams to include indolin-2-ones provides a Vilsmeier-type methodology for the construction of biindolyl systems, which are of considerable current interest.37,39-43 In this situation, the initially formed imines are indolenines, which readily isomerize to the related 2-indolyl derivatives.43 In view of our general interest in activated indoles, as well as a specific interest in continuing to synthesize structures containing indoles directly linked to each other, we investigated not only reactions with indolinone itself but also with substituted derivatives. These were variously methoxy-substituted at C-4 and C-6, and in some cases substituted also at C-3 with methyl, phenyl, or dithiolan groups. 

Recently Liu and coworkers used (porphyrin)iron(III) chloride complex 96 to promote 1,5-hydrogen transfer/SHi reactions of aryl azides 95, which provided indolines or tetrahydroquinolines 97 in 72-82% yield (Fig. 24) [148]. The reaction starts probably with the formation of iron nitrenoids 95A from 95. These diradicaloids undergo a 1,5- or 1,6-hydrogen transfer from the benzylic position of the ortho-side chain. The resulting benzylic radicals 95B react subsequently with the iron(IV) amide unit in an Sni reaction, which liberates the products 97 and regenerates the catalyst. /V,/V-Dialkyl-w// o-azidobenzamides reacted similarly in 63-83% yield. For hydroxy- or methoxy-substituted indolines 97 (R2=OH or OMe) elimination of water or methanol occurred from the initial products 97 under the reaction conditions giving indoles 98 in 74—78% yield. 

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>. 

J.M. Cook et al. accomplished the enantiospecific total synthesis of the indole alkaloid tryprostatin A." The substituted indole nucleus was assembled at the beginning of the synthesis, and the necessary arylhydrazone was prepared via the Japp-Kiingemann reaction using the diazonium salt derived from m-anisidine and the anion of ethyl-a-ethylacetoacetate. The regioselectivity of the Fischer indoie synthesis favored the 6-methoxy-3-methylindole-2-carboxylate regioisomer in a 10 1 ratio. 

The total synthesis of (-)-fuchsiaefoline was accomplished in the laboratory of J.M. Cook using the Larock indole synthesis to prepare the key precursor 7-methoxy-D-tryptophan in enantiopure form. The propargyl-substituted Schollkopf chiral auxiliary was reacted with 2-iodo-6-methoxyaniline in the presence of 2 mol% Pd(OAc)2 to give the expected indole in good yield. Interestingly, the Bartoli indole synthesis gives /-substituted indoles only in moderate yield. 

Zhou, H., Liao, X., Cook, J. M. Regiospecific, Enantiospecific Total Synthesis of the 12-Alkoxy-Substituted Indole Alkaloids, (+)-12-Methoxy-Na-methylvellosimine, (+)-12-Methoxyaffinisine, and (-)-Fuchsiaefoline. Org. Lett. 2004, 6, 249-252. 

Substituted indoles may be used, but must be protected (e.g. methoxy instead of hydroxy). Substitutions on the phenyl ring will result in the formation of substituted 3-(dialkylamino-methyl)-indoles such as 4-methoxy-gramine. 

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. 

A similar synthesis of both 2- and 3-substituted indoles has been done using iV-Boc-o-alkylanilines as the reactants <90SL207,9iS87i>. Use of DMF gives indoles unsubstituted at C2 while A -methoxy-A-methylamides afford 2,3-disubstituted indoles. 

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