Indole synthesis - Organic chemistry

2 methyl indole synthesis essay

2-Methylindole - supplier and manufacturer 2-Methyl …

Crystal data, data collection and structure details are summarized in Table 2. All H atoms were positioned geometrically and refined using a riding model with C—H = 0.05–0.99 Å and (H) = 1.2 or 1.5(C).

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We thank the National Institute of General Medical Sciences (GM070620 and GM079593) and the National Institutes of Health Kansas University Center of Excellence in Chemical Methodology and Library Development (P50 GM069663) for their generous financial support. We also thank Dr. Feng Shi for his help in the preparation of some of the aryne precursors.

We thank the National Institute of General Medical Sciences (GM070620 and GM079593) and the National Institutes of Health Kansas University Center of Excellence in Chemical Methodology and Library Development (P50 GM069663) for their generous financial support. We also thank Dr. Feng Shi for his help in the preparation of some of the aryne precursors.


New 3H-Indole Synthesis by Fischer’s Method

With optimized conditions in hand (, entry 6), we have explored the scope and limitations of our methodology. Suitable indole substrates were easily prepared by the esterification of commercially available 2-indolecarboxylic acids. It was found that indoles containing electron-donating groups generally resulted in lower yields than the unsubstituted indole (, entries 2-6). Possibly, the electron-donating groups decrease the acidity of the indole, resulting in a weaker nucleophile. In fact, for all substrates containing a methoxy group, it has been observed that a significant amount of the starting material remains after 24 h. Low yields are also obtained with indole 1g, a substrate containing a highly electron-withdrawing group. It is believed, however, that steric crowding of the nitro group around the nucleophilic nitrogen center is the main reason for the observed decrease in yield (entry 7). On the other hand, a variety of 5-haloindole-2-carboxylates have afforded good yields of the desired products (entries 8-10). Interestingly, even better results are observed when the halogen occupies the 3-position of the indole (entries 11-13). This trend is also observed in substrates 1n and 1o, whose 3-positions are substituted (entries 14 and 15) and near quantitative yields are observed. This may be attributed to steric effects, in that a substituent at the 3-position can better help direct the electrophilic ester moiety for intramolecular attack by the intermediate aryl carbanion. As expected, replacement of the N-H with a N-methyl group prevented any formation of the desired N-annulated product (entry 16).

yield by a Fischer indole synthesis reaction of o,m ..

With optimized conditions in hand (, entry 6), we have explored the scope and limitations of our methodology. Suitable indole substrates were easily prepared by the esterification of commercially available 2-indolecarboxylic acids. It was found that indoles containing electron-donating groups generally resulted in lower yields than the unsubstituted indole (, entries 2-6). Possibly, the electron-donating groups decrease the acidity of the indole, resulting in a weaker nucleophile. In fact, for all substrates containing a methoxy group, it has been observed that a significant amount of the starting material remains after 24 h. Low yields are also obtained with indole 1g, a substrate containing a highly electron-withdrawing group. It is believed, however, that steric crowding of the nitro group around the nucleophilic nitrogen center is the main reason for the observed decrease in yield (entry 7). On the other hand, a variety of 5-haloindole-2-carboxylates have afforded good yields of the desired products (entries 8-10). Interestingly, even better results are observed when the halogen occupies the 3-position of the indole (entries 11-13). This trend is also observed in substrates 1n and 1o, whose 3-positions are substituted (entries 14 and 15) and near quantitative yields are observed. This may be attributed to steric effects, in that a substituent at the 3-position can better help direct the electrophilic ester moiety for intramolecular attack by the intermediate aryl carbanion. As expected, replacement of the N-H with a N-methyl group prevented any formation of the desired N-annulated product (entry 16).

Methyl 1H-indole-2-carboxylate CAS#: 1202-04-6

Initial experiments began with ethyl indole-2-carboxylate as our test substrate, but little success was realized using conditions similar to those of our previous annulation chemistry. Switching to the methyl ester, however, produced a slight increase in yield of the desired product (, entry 1). It was not until we switched to 1,2-dimethoxyethane (DME) as a solvent that decent results were obtained (entry 3). The addition of various bases was examined and a significant improvement in yield was realized when two equiv of Cs2CO3 were utilized (entry 6). The success of this base over others (entries 7-9) may be attributed to its superior solubility in DME. The success of aryne annulation chemistry often depends heavily on the relative rate of aryne formation versus bimolecular coupling of the substrate and the aryne. For that reason, both the quantity and the nature of the fluoride source, as well as the solvent and temperature, are often critical. CsF has generally been the most popular source of fluoride used in benzyne chemistry and, in fact, it seems to work best for our methodology. Other sources of fluoride, such as tetrabutylammonium reagents have been examined. However, the overall yields declined (entries 13 and 14), even though these fluorides are more soluble in DME.