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Larock indole synthesis - Wikipedia

Larock Indole Synthesis - SynArchive

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In a new version of the Fischer indole synthesis, ..

Transition-metal catalysts are commonly used to effect site-selective carbon-carbon and carbon-heteroatom bond formation. One synthetically attractive application of this idea concerns synthesis of the indole skeleton, which can be constructed through cross-coupling reactions of appropriately substituted 2-alkynyl, 2-alkenyl, and 2-allyl anilines. Palladium in particular has seen wide use as a transition-metal catalyst in this context, because of its versatility and effectiveness in establishing both C–C and C–X bonds. In the presence of a palladium catalyst, a variety of coupling partners combine to form aromatic indoles. Figure 1 outlines the known retrosynthetic disconnections one can envision based on the known coupling chemistry of alkenes and anilines.

Larock indole synthesis - WikiVisually

In 1991, Larock and co-workers reported the synthesis of 2,3-disubstituted indoles by the Pd-catalyzed annulation of 2-iodoanilines and disubstituted alkynes (). In contrast to other indole syntheses such as those from Fukuyama, Cacchi, or Furstner, the Larock procedure does not require a substituent or a protecting group on the aniline nitrogen. The reaction typically tolerates a range of functional groups on either partner and the heteroannulation is highly site selective. In general, the Larock heteroannulation favors the product in which the bulkier alkyne substituent resides at the C(2) position of the indole. One example has appeared where reversed regioselectivity was observed, but the origin of this process remains unknown. Thus, a limitation to the Larock process arises with alkynes that bear terminal substituents with similar steric demands. A recent illustration of this limitation to the Larock indole synthesis was reported where poor selectivities were observed when alkynes bearing cycloalkyl and aryl groups were employed. Nevertheless, the reaction has been widely used in industrial and academic settings (on multi-kilogram scale), and the transformation has achieved named reaction status.

Fischer Indole Synthesis - Organic Chemistry Portal

Mechanism of the Fischer Indole Synthesis

Although Larock and co-workers demonstrated the usefulness of silylated alkynes in this reaction, subsequent transformations of the resulting 2-silyl indoles have been limited to desilylation, bromination or simple Heck-type cross-coupling with alkenes. The ability to exploit the silyl group both for site selectivity in the annulation as well as a functional handle for further synthetic elaboration would add significant value to this reaction.

In addition, more modern approaches to the synthesis of disubstituted indoles have emerged that take advantage of the current advances in transition metal chemistry. Some newer methods to construct 2,3-disubstituted indoles include the radical cyclization of 2-alkenylisocyanides, reductive cyclization of acylamido carbonyl compounds, cyclization of N-(2-halophenyl)allenamides, palladium-catalyzed cyclization of 2-alkynyltrifluoroanilines in the presence of an alkenyl- or aryl halide, and palladium-catalyzed cyclization of 2-iodoanilines with disubstituted alkynes. Among these, the Larock indole synthesis has emerged as a versatile and powerful method for the formation of substituted indoles.

A Tandem Ru Catalyzed Hydrogen-Transfer Fischer Indole Synthesis A

Fischer indole synthesis - Wikipedia

The proposed mechanism of this reaction involves several key steps (). Larock has suggested that the reaction begins with coordination of chloride to Pd0 to form an anionic palladium species that undergoes oxidative addition to the aryl iodide. Next, coordination of the alkyne to the Pd atom occurs (46) followed by syn migratory insertion. Displacement of the iodide by nitrogen affords palladacycle 47 that reductively eliminates to give the indole product and regenerate the palladium catalyst. It is worth noting that this mechanistic proposal is not supported by any experiments and remains speculative.

Although Larock and co-workers demonstrated the usefulness of silylated alkynes in this reaction, subsequent transformations of the resulting 2-silyl indoles have been limited to desilylation, bromination or simple Heck-type cross-coupling with alkenes. The ability to exploit the silyl group both for site selectivity in the annulation as well as a functional handle for further synthetic elaboration would add significant value to this reaction.

The Fischer indole synthesis is a chemical reaction that produces the ..
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  • Bartoli indole synthesis, Bartoli reaction; Barton reaction; ..

    How to Cite. 2010. Larock Indole Synthesis. Comprehensive Organic Name Reactions and Reagents. 385:1717–1721.

  • Larock indole synthesis; Lebedev process;

    Larock Indole Synthesis

  • Fischer indole synthesis - Revolvy

    Larock Indole Synthesis.

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Larock indole synthesis – Larock indole synthesis mechanism

From a retrosynthetic point of view, palladium-catalyzed indole formation has extremely broad scope. Alkynyl anilines are most commonly used for indole formation, because they are easily constructed from -haloanilines through Sonogashira coupling. In many cases, cyclization to form indoles is spontaneous under Sonogashira coupling conditions (Eq. 6).

[Named Reaction #5]: Fischer Indole Synthesis : chemistry

Unlike other books on name reactions in organic chemistry, Name Reactions, A Collection of Detailed Reaction Mechanisms and Synthetic Applications focuses on the reaction mechanisms.

The Fischer indole synthesis is a chemical reaction that ..

Bond c (Eq. 2) may be established through the coupling of a nucleophilic enamine and electrophilic aryl halide. Enamines generated from aldehydes and 2-haloanilines couple smoothly to give indoles (Eq. 10).

Reissert indole synthesis , Larock ..

Although a number of other metals have been applied to the synthesis of indoles, none match the versatility and substrate scope of palladium. The majority of indole-formation reactions that employ other metals use 2-alkynyl anilines, which typically must be prepared through Sonogashira coupling with palladium anyway. In a few cases, however, other metals are useful to accomplish couplings that are not possible with palladium.

Yamanaka–Sakamoto indole synthesis Larock indole ..

Reported is a palladium-catalyzed synthesis of -aryl indoles from the reaction of ­diaryl amines with olefins by a hydroamination–C–H activation route. In recent years, the traditional methods, for example, the venerable century-old Fischer indole synthesis, among other textbook reactions, have been superceded by a barrage of methodologies based on transition-metal-catalyzed heteroannulation processes originating with Larock, with significant contributions by Buchwald, Ackermann, Glorius, Fagnou, among others (see: . , , 3434; , , 9098; , , 12426). The present methodology takes advantage of the Fujiwara–Moritani reaction (hydroamination of olefins) together with a precedented aryl C–H activation to achieve the -aryl indole synthesis. Although a comparison to another ruthenium-based photocatalytic method is given, the significance of the present route in assessment to plethora of recently similar established methods is unfortunately not made and would require reading of about 30 references cited in this report.

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