Functionalized indole synthesis

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

Donor substituents on the vinyl group further enhance reactivity towards electrophilic dienophiles. Equations 8.6 and 8.7 illustrate the use of such functionalized vinylpyrroles in indole synthesis[2,3]. In both of these examples, the use of acetyleneic dienophiles leads to fully aromatic products. Evidently this must occur as the result of oxidation by atmospheric oxygen. With vinylpyrrole 8.6A, adducts were also isolated from dienophiles such as methyl acrylate, dimethyl maleate, dimethyl fumarate, acrolein, acrylonitrile, maleic anhydride, W-methylmaleimide and naphthoquinone. These tetrahydroindole adducts could be aromatized with DDQ, although the overall yields were modest[3]. 

An important extension of this indole synthesis is the functionalization of the intermediate of indole. For example, acylation of the intermediate is possible (Scheme 10.7).68... 

Indole Ring Functionalization Movassaghi Synthesis of the Asperazine Core... 

A type Ilac synthesis of functionalized pyrroles was developed that adapted the Larock indole synthesis <06OL5837>. For example, treatment of iodoacrylate 19 and trimethylsilylphenylacetylene 20 with palladium acetate led to the formation of pyrrole-2-carboxylate 21 with excellent regioselectivity. 19 was prepared by iodinating (N-iodosuccinimide) the corresponding commercially available dehydroamino ester. 

Synthesis of Functionalized Indole- and Benzo-Fused Heterocyclic Derivatives through Anionic Benzyne Cyclization... 

Abstract The development of a new method for the regioselective synthesis of functionalized indoles and six-membered benzo-fused N-, O-, and S-heterocycles is reported. The key step involves the generation of a benzyne-tethered vinyl or... 

Scheme 3. Synthesis of 3,4-functionalized indole derivatives 10 and 11 by Alder-ene reactions, i) X=Y, THF, 67 °C [X=Y H20=N+Me2L,...

The next three procedures provide useful synthetic intermediates. A stereospecific synthesis of ETHYL (Z)-3-BROMO-2-PROPENOATE affords an alternative vinyl bromide partner for the coupling chemistry in the preceding procedure. A very simple but elegant illustration of the flash vacuum pyrolysis technique is used to prepare BENZOCYCLOBUTENONE from o-toluoyl chloride. Another member of the functionalized indole family of synthetic intermediates is presented in a four-step procedure for 5-METHOXYINDOLE-2-ACETIC ACID METHYL ESTER. 

Various organolithium intermediates may be posmlated for the synthesis of functionalized indoles and other heterocyclic compounds, from substituted Af-allylanilines (331a-c) or the cychc analog 332, on treatment with f-BuLi. For example, in equation 81 intermediate 333, derived from 331a, was quenched with deuterium oxide. Participation of benzyne metallated intermediates, such as 334, derived from 332, is surmised in equation 82 and other processes. The products of equations 81 and 82 can be characterized by H and NMR spectra . 

The Fischer indole synthesis is quite tolerant of additional functional groups in the starting material. Thus reaction of 4-dimethylaminocyclohexanone (18-2) with phe-nylhydrazine (18-1) in acetic acid leads directly to cyclindole (18-3) [18], a compound described as an antidepressant. A shghtly different approach is used to prepare the fluorinated analogue. The tricyhc indole (18-5), in this case, is obtained by reaction of 2,4-diiluorophenylhydrazine (18-4) with 4-hydroxy-cyclohexanone. The hydroxyl... 

The Fischer indole synthesis is the conversion of an Af-arylhydrazone to an indole with elimination of ammonia (equation 88). This method is of very broad scope, and is able to accomodate a wide variety of functionalized and unfunctionalized 2- and 3-side chains as well as substituents in the carbocyclic ring (B-70MI30605,72HQ25-D232). Ironically, the parent 2,3-unsubstituted indoles are difficult to obtain via the Fischer method. Indole itself was not successfully made by the Fischer method until 1976, and then only using a high temperature (290-300 °C) procedure (76JOC1877). 

The fact that benzene derivatives are much more generally accessible than pyrroles has relegated pyrrole annelation to a relatively minor role in indole synthesis. Nevertheless the concept provides a viable synthetic approach and the existing methods serve as useful prototypes. One strategy is to build up an appropriately functionalized side-chain and complete indole formation by electrophilic substitution-aromatization. Reactions (135)-(137) illustrate this type of approach (79TL3477, 79JA257, 73JPR295). 

Sulfur-substituted 3-vinylpyrroles generated from A -methyl-3-thioace-tylpyrrole have been used to accomplish the synthesis of functionalized indoles by Diels-Alder cycloaddition. In the reactions with MA, NPMI, and naphthoquinone the [4 + 2]-cycloadducts were obtained with low to moderate yields and directly transformed to the corresponding indoles by treatment with DDQ (91CPB489). 

In a similar heterocyclic quinodimethane ring construction strategy, the hexacyclic adducts (64) were isolated in good yield upon condensation of appropriately functionalized indole imines with ( )-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid chloride (Equation (35)) (88JA2242). In a demonstration of the utility of this new method for indole alkaloid synthesis, further transformations conducted on compound (64 R = R2 = H, R3 = Et) were shown to lead to ( —)-16-methoxy-tabersonine. 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

He and his students developed C-alkylation with quaternary ammonium salts and nucleophilic displacements on such salts, including the stereochemistry. His name is immediately associated with important innovations in the use of polyphosphoric acid for inter- and intramolecular condensations, cyclizations, and functional conversions in organic chemistry. He pioneered the use of boron trifluoride as an efficient catalyst in the Fischer indole synthesis and discovered new reactions of anils, including Diels-Alder reactions. He and his students delineated the requirements for disproportionation of tertiary amines. He developed the synthesis and chemistry of arylboranic acids. One of his fundamental ideas was for the incorporation of sufficient boron into organ-specific drugs that they could then be... 

At the early stage of Heathcock s biomimetic total syntheses of discorhabdins [108], a 5-ejco Heck cyclization was employed for the synthesis of 3,6,7-functionalized indole. As highlighted in Scheme 42, when precursor 237 was exposed to catalytic palladium acetate, tri-o-tolylphosphine, and stoichiometric base, indole 238 was smoothly produced in 89% yield. Subsequently, the total syntheses of discorhabdin C (239) and discorhabdin E (240) were accomplished using indole 238 as the common intermediate. 

In the indole synthesis, the authors reported the necessity to avoid protons during the titanium benzylidene formation prior to the capping with the support-bound ester. It was found fhat fhe possibility of proton transfer in this stage of fhe reaction would lead to an exhaustive reduction of fhe difhioacetal function to a mefhyl group. Thus, fhe orfho-nucleophile (Boc-NH-functions) had to be protected by silylation. 

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