Methyl 1 -methoxyindole-3-carboxylate

In fact, iodination of methyl l-methoxyindole-3-carboxylate (109), a wasabi phytoalexin (98P1959), with KI and NaI04 (60LA84, 911OC5903) in TFA-HjO provides methyl 5-iodo-l-methoxyindole-3-carboxylate (110,72%) predominantly... 

Pedras and co-workers (98P1959) isolated a phytoalexin from Wasabi (Wasabia japonica, syn. Eutrema wasabi) and determined its structure to be methyl l-methoxyindole-3-carboxylate (109) (Scheme 38). Compound 109 had already been synthesized by Acheson and co-workers [78JCS(P1)1117] in ten steps from o-nitroaniline. Pedras and co-workers (98P1959) combined our tungstate method and Acheson s work, and synthesized 109 in 9% overall yield but in an impure state. 

A mixture of 9.5 g pyrrolyl-2-aldehyde, 29.2 g dimethyl-succinate and NaH (9.6 g of 50% suspension in oil) in 100 ml benzene is stirred at room temperature 6 hours, cooled and carefully acidified with glacial acetic acid. Add water and ether and dry, evaporate in vacuum or work up (JACS 72,501 (1950), JCS 1025(1959)) to get ca. 17 g (80%) 3-methoxycarbonyl-4-(2 -pyrrolyl)-3-butenoic acid (I) (recrystallize-acetone-benzene). A mixture of 12 g (I), 7 g sodium acetate and 70 ml acetic anhydride is left overnight at room temperature with occasional shaking. Then gradually raise the temperature to 70-75° over 2 hours, maintain for 4 hours and work up (see JCS 1714(1955), 986( 1958)) to get ca. 8 g (60%) methyl-4-acetoxy-indole-6-carboxylate (II) (recrystallize-petroleum ether). If desired, this can be converted to 4-OH-indole-6-COOH and 4-methoxyindole-COOH as described in the ref. or decarboxylated as described elsewhere here. If the 1-methyl cpd. is used, 1-Me-indole results. 

Hydrolysis of 1-acetoxy- or l-hydroxy-3-cyanoindole (115) by hydrogen peroxide or 1 M sodium hydroxide gave the corresponding amide, while QM sodium hydroxide gave the 3-carboxylic acid which decomposed rapidly at room temperature with diazomethane, the last compound gave the stable methyl l-methoxyindole-3-carboxylate [78JCS(P1)1117]. 1-... 

The position of the sugar residue in the dihydroindole portion can be determined by methylation of the pigment with diazomethane and subsequent alkaline degradation of the resulting neobetanin derivative. In the case of 5-0-glycosides, 5-hydroxy-6-methoxyindole-2-carboxylic acid is obtained, whereas the 6-O-glyco-sides yield 6-hydroxy-5-methoxyindole-2-carboxylic acid (47,48). The indole carboxylic acids are easily identified by TIjC. 

The VNS reaction of 4-nitroanisole with ethyl chloroacetate followed by the Knoevenagel condensation of the product with acetaldehyde affords a-(2-nitrophenyl)crotonate, which in the presence of f-BuOK in ferf-butanol undergoes cyclization into V-hydroxyindole-3-carboxylate (Scheme 76). Further alkylation of the latter compound with methyl iodide results in Af-methoxyindole. It is worth mentioning that in this reaction a partial loss of the alkene chain does happen to occur [194]. A similar phenomenon has been observed earlier in our laboratory [195]. 

A soln. of K-nitrosodisulfonate and NaHCOg added simultaneously with ethyl acetate to a stirred aq. soln. of methyl 3-hydroxy-4-methoxyphenylalaninate, and the product isolated after 0.5 hr. from the 2-phase system methyl 5-hydroxy-6-methoxyindole-2-carboxylate. Y 68%. M. E. Wilcox et ah, Helv. 4-8, 252 (1965). 

Dehydrogenation of indoUnes using DDQ has been used to prepare 6-nitroindole (benzene, reflux, 86%) [32], 7-bromo-5-nitroindole (98%) [33], 6-azido-4,5,7-trif-luoroindole (benzene, 88%) [34], 4,5,6,7-tetrahydroindole (benzene, reflux, 68%) [35], methyl l-acetyl-2-cyclopro-pyl-5-methoxyindole-3-carboxylate (toluene, reflux, 87%) [36], 5,6-dicyano-l-methylindole (benzene, reflux, 97%)... 

Nevertheless, there are several other oxidation (dehydrogenation) routes to indoles from indolines. In a series of papers, Somei and colleagues used sodium tungstate to synthesize A-hydroxyindole derivatives from the corresponding indolines (Scheme 11, equations 1 and 2) [64, 103-107]. The simple l-hydroxy-6-nitroindole [106] and 4-, 6-, and 7-ethoxy-l-methoxyindoles were synthesized in similar fashion [107]. Pedras and coworkers employed the Somei method to prepare the natural phytoalexin methyl l-methoxyindole-3-carboxylate [108], and McNab and... 

Additional halogenation of 78 and 81 exhibits interesting results [28]. Bromination (1.3-mol eq.) of the former in AcOH provides methyl 6-bromo-5-iodoindole-3-carboxylate (82, 56%) and the corresponding carboxylic add (83, 18%). On the other hand, bromination of the latter gives complex mixtures of products under various reaction conditions. Relatively clean reaction takes place with Br2 (1.3-mol eq.) in AcOH at 100 °C providing methyl 6-bromo- (84, 17%), methyl 2-bromo-5-iodo-l-methoxyindole-3-carboxylates (85, 33%), 5-iodo-l-methoxyindole-3-carboxylic acid (86, 7%),... 

Friedel-Crafts acylation of 77b with chloroacetyl chloride and AICI3 in nitrobenzene provides cleanly methyl 5-chloroacetyl- (90a, 52%) and 6-chloroacetyl-l-methoxyindole-3-carboxylates (91a, 20%) with the ratio of 2.5 1 (Scheme 11) [28]. Under similar reaction conditions, Nakatsuka and co-workers reported the chloroacetylation of methyl l-methylindole-3-carboxylate (89) to give 90b and 91b in the ratio of 3 1 [29]. Comparing these results with ours, it would be safe to conclude that the introduction of a methoxy group onto the N(l) prefers the 6- to 5-substitution in Friedel-Crafts acylation. 

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