Aniline derivatives indoles from

The Hegedus indole synthesis involves one of the earlier (formal) examples of olefin hydroamination. An ortho-vinyl or ortho-nllyl aniline derivative 1 is treated with palladium(II) to deliver an intermediate resulting from alkene aminopalladation. Subsequent reduction and/or isomerization steps then provide the indoline or indole unit 2, respectively. 

The aniline derivative 332, prepared from 2-fluoro-6-nitrotoluene, was transformed through successive reactions as shown in Scheme 60 to give the functionalized indole 333. It was then reduced with LiAlH4 to the dimethylaminopropyl derivative which was quaternized with Mel to the trimethyl ammonium salt 334. Subsequent cyclization and functionalization afforded the pyrroloquinoline 335. The latter could be transformed to the tetracyclic acid 336 (90JHC2151). (Scheme 60)... 

Meerwein reactions can conveniently be used for syntheses of intermediates which can be cyclized to heterocyclic compounds, if an appropriate heteroatom substituent is present in the 2-position of the aniline derivative used for diazotization. For instance, Raucher and Koolpe (1983) described an elegant method for the synthesis of a variety of substituted indoles via the Meerwein arylation of vinyl acetate, vinyl bromide, or 2-acetoxy-l-alkenes with arenediazonium salts derived from 2-nitroani-line (Scheme 10-46). In the Meerwein reaction one obtains a mixture of the usual arylation/HCl-addition product (10.9) and the carbonyl compound 10.10, i. e., the product of hydrolysis of 10.9. For the subsequent reductive cyclization to the indole (10.11) the mixture of 10.9 and 10.10 can be treated with any of a variety of reducing agents, preferably Fe/HOAc. 

The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2-symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of a-arylamino imine tautomers prepared from aniline derived a-arylamino ketones, has been used by Menendez and co-workers for the preparation of 2-arylindoles <06SL91>. 

Because substituted anilines are widely available, they are ideal starting materials for the synthesis of indoles. Although anilines are often the precursors of the hydrazones used in the Fischer cyclization, more direct methods for conversion of anilines to indoles would be highly desirable. Such a process would, in general, have to involve some method for specific o -substitution of the aniline derivative. In the most successful method of this type which has been developed to date, a specific rearrangement effecting o-substitution is the key to a synthetic scheme which constructs indoles from anilines via anilinosulfonium ions. The procedure, which in appropriate circumstances can be carried out without isolation of the intermediates, involves oxidation of the aniline to an A-chloroaniline, reaction with a thiomethylmethyl ketone and a weak base, followed by cyclizative condensation (equation... 

Conjugated derivative 84b was obtained in a two-step reaction from bis(phenacyl)aniline via indole 83 by treatment with PPA.59... 

The indole system has been the most extensively studied, particularly in regard to the mechanism of cyclization." It is noteworthy that in some instances an isomerization of the anilinoketone occurs, viz., R CH(NHRX OR" to R COCH(NHR)R From a preparative standpoint, the method is valuable in the formation of several indoles in excellent yields, e.g., 2,3-dimethyl indole (85%)" and 2-ethyl-3-methylindole (92%). Condensation of aniline derivatives of 2-chlorocyclohexanone yields the corresponding tetrahydrocarbazoles... 

Indok synthesis. Gassman and van Bergen have used a modification of the above-mentioned procedure for synthesis of 2-substituted indoles from anilines. The aniline IS treated as above with a chlorinating reagent at — 65° and then an equivalent of methyl-thio-2-propanone at the same temperature. An equivalent of a base (usually triethyl-amine) is added. Workup affords the indole derivative (2) in 60-70% yield. The thio-methyl group is removed with Raney nickel (>70% yield). The keto sulfide can be varied thus nse of methyl phenacyl sulfide [CH3SCH2C(=0)C5H5]4 in the synthesis leads to 2-phenylindoles. 

Indole derivatives are biologically important natural products. Many efforts have been made to achieve the synthesis of this motif. Various innovative and powerful methodologies for the synthesis of indole derivatives have been developed. Recently, Glorius and co-workers reported an efficient oxidative synthesis of indoles from N-arylenamines using Pd(OAc)2 as a catalyst and Cu(OAc)2 as a stoichiometric oxidant (Equation 11.38) [77]. This method represents an excellent example of constructing C—C bonds by direct use of two C—H bonds. This conversion of anilines into indoles can also be carried out in a one-pot sequence. 

Quinoline was converted in good yield to nicotinic acid (Sturrock et al., 1960). With indoles, the pyrrole ring opens to give aniline derivatives, as in the formation of 2-aminobenzaldehyde and anthranilic acid from indole (Equation 5.44) (Jurs, 1966). 

Among other classic but useful indole syntheses are those of Bis-chler (1892) and Madelung (1912). In the Bischler synthesis, an aniline derivative is alkylated by an alpha-haloketone. Heating the product (9.81) effects the electrophilic attack of the carbonyl group on the benzene ring the loss of water from the product gives the indole structure (Scheme 9.38). 

In 2003, Alper and co-workers, based on an earlier, reported the synthesis of substituted tosyl-indoles from substituted anilines and isopropylsulfides, introduced a practieal way for the elaboration of multigram scale of the otherwise difficult accessible methyl 7-chloroindole-4-carboxylate, based on the desulfurization and cyclization of a prior Sommelet-Hauser rearranged produet 41, derived from the reaction of methylsulfide 39 with o-chloroaniline derivative 40. 

In connection with an investigation of the fluorescent characteristics of derivatives of 2,2 -bithienyls, a number of heterocyclic substituted thiophen derivatives, such as (199)—(204) and their formyl derivatives, have been prepared. The quinoline derivatives were obtained from the appropriate 2-lithiobithienyl and quinoline, whereas the benzimidazolyl, benzoxazolyl, and benzothiazolyl derivatives were prepared by the condensation of a cyanothiophen or 5-cyano-2,2 -bithienyl with the appropriate aniline derivative. (204) was prepared through a Fischer indole synthesis. ... 

Reddy and colleagues devised a novel method for the divergent synthesis of 2,3-disubstituted indoles or 2,4,5-trisubstituted pyrroles from a-diazoketone 126. In the presence of copper(II) triflate, treatment of a-diazoketone 126 with enamine 129 gave pyrrole 130 if 126 was instead treated with aniline derivative 127, indole 128 resulted. The study culminated in the formal synthesis of indole-containing natural product homofascaplysin C (130L464). 

Reversal of enantioselectivity in Cu-chiral bipyridine-catalyzed asymmetric ring-opening reactions of meso-epoxides with indole and aniline derivatives is observed compared to Sc-chiral bipyridine-catalyzed reactions, where the same chiral ligand is used (Scheme 32). " It was revealed from X-ray crystal structural analysis that a square pyramidal structure for the Cu° complex and a pentagonal bipyramidal... 

Recently, Wu group synthesized a series of novel iV-(2-pyridyl)indoles from alkynes and aniline derivatives via a heterogeneous Pd-catalyzed oxidative C-H activation reaction [10]. In the presence of Pd/Ce02 catalyst, only catalytic amounts of Cu(II) and air as co-oxidant were required, delivering the desired indoles in moderate to excellent isolated yields (Scheme 14.8). As shown, both... 

Indole and isoquinolone nuclei are prominent structural units frequently found in numerous natural products and pharmaceutically active compounds. Thus, the search for new methodologies to obtain these scaffolds with different substitution patterns is a current major objective in organic synthesis. Similar to benzofuran synthesis, Aluraez et al. observed that the palladium-catalyzed cascade intramolecular alkyne aminopaUadation/intermolecular Heck-type coupling reaction under oxidative conditions is an efficient methodology for the synthesis of indole 217 and isoquinolone 219 derivatives, starting from readily available aniline 216 or benzamide 218 substrates and functional alkenes [77] (Scheme 6.60). 

Aniline derivatives have been used to synthesize the indoline system. A large variety of indoline alkaloid substructures are available in a very efficient way. Enamine derivatives such as 39 bearing electron withdrawing substituents on the olefinic double bond were transformed in high yields (Scheme 7). Two syn/anti isomers 41 and 42 were isolated. The isomeric ratio of the final products was influenced by a photostationary equilibrium between the substrates 39 and 40. The reaction was applied to the synthesis of a variety of derivatives of the alkaloid aspidospermidine." In this context, the cyclization products 43 were transformed into the polycyclic indole derivatives 44,45, and 46. Polycyclic indolone compounds 48 have been successfully produced by cyclization of enaminone derivatives 47 carrying a quinoline substituentIn these cases and contrary to the examples 41,42, and 43, the products 48 resulted from an oxidation of the cyclization product (also compare the formation of 30 in Scheme 5). 

EtAlCb catalyzes the Friedel-Crafts acylation of alkenes with acid chlorides, the formal [3 + 2] cycloaddition of alkenes with cyclopropane-1,1-dicarboxylates (eq 21), the Friedel-Crafts alkylation of anilines and indoles with ct-aminoacrylate esters, and the formation of allyl sulfoxides from sulfinyl chlorides and alkenes. EtAlCU induces the Beckmann rearrangement of oxime sulfonates. The cationic intermediates can be trapped with enol silyl ethers (eq 22). EtAlC is the preferred catalyst for addition of the cation derived from an a-chloro sulfide to an alkene to give a cation which undergoes a Friedel-Crafts alkylation (eq 23). ... 

Studies on the Bischler-Napieralski cyclization of A -acetyltryptamine in the presence of indole have led to the isolation of numerous products, among which the indolocarbazole 186 could be found in 3.5% yield. This outcome was rationalized as a result of the intermediacy of a spiroindolenine species formed under these conditions [89H(28)175]. During detailed studies on the polymerization of indole, formation of a low yield of the related indolo[3,2-h]carbazole 187 was discovered in the product mixture originating from the treatment of indole with p-toluenesulfonic acid at elevated temperature [88JCS(P1)2387]. In an investigation of the condensation of p-benzoquinone with 4-substituted anilines, an indolo[3,2-h]carbazole derivative has been reported to be formed in 2% yield (80JOC1493). 

Frejd and co-workers utilized a different tactic for aniline cyclization by first employing a Heck-Jeffery protocol under solvent-free conditions to prepare o-amino dehydrophenylalanine derivatives from o-aminoaryl iodides with the former undergoing a spontaneous la cyclization-elimination sequence to afford 2-methoxycarbonyl indoles <06S1183>. Dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST) was used by the Okuma group to promote the cyclization of o-vinyl-A-p-toluenesulfonylanilide to N-tosylindole <06CL1122>. 

In terms of economical synthetic approaches to indoles, the synthesis of this heterocycle from anilines and trialkylammonium chlorides was effected in an aqueous medium (H20-dioxane) at 180°C in the presence of a catalytic amount of ruthenium(III) chloride hydrate and triphenylphosphine together with tin(II)chloride <00TL1811>. Muchowski devised a novel synthetic route to indole-4-carboxaldehydes and 4-acetylindoles 86 via hydrolytic cleavage of W-alkyl-5-aminoisoquinolinium salts 85 to homophthaldehyde derivatives upon heating in a two phase alkyl acetate-water system containing an excess of a 2 1 sodium bisulfite-sodium sulfite mixture <00JHC1293>. 

Gronowitz adapted this technology to one-pot syntheses of indole-3-acetic acids and indole-3-pyruvic acid oxime ethers from A-BOC protected o-iodoanilines [328, 329]. Rawal employed the Pd-catalyzed cyclization of A-(o-bromoallyl)anilines to afford 4- and 6-hydroxyindoles, and a 4,6-dihydroxyindole [330], and Yang and co-workers have used a similar cyclization to prepare 8-carbolines 287 and 288 as illustrated by the two examples shown [331]. The apparent extraneous methyl group in 288 is derived from triethylamine. 

Scheme 12 Synthesis of indole derivatives from styrene-type anilines...

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