N-Acyl indoles

N-Acylated indoles are converted into tricyclic compounds 211 in the presence of samarium diiodide (2.5 eq.) along with hexamethylphosphoramide (10 eq.) and phenol (2.0 eq.) as proton source <20030L4305>. 

N-Acylated indoles 1520 furnished tricyclic compounds 1521 in the presence of samarium diiodide (2.5 equiv) in tetrahydrofuran along with an excess of hexamethylphosphoramide (10 equiv) and phenol (2 equiv) as proton source (Equation 311) <20030L4305>. Whereas methyl ketone 1520 (R = Me) smoothly cyclized to compound 1521 (in 73% yield), the corresponding aldehyde 1520 (R = H) provided compound 1521 only in low yield (28%). 

Polycyclic products 1523, 1524,1526, and 1528 were formed with essentially perfect diastereoselectivity and good to excellent yields when the reactions of N-acylated indoles 1522, 1525, and 1527 were performed in the absence of HMPA (Scheme 291, Equations 312 and 313) <20030L4305>. 

Phthallmides in which the nitrogen is connected by an alkyl chain to the 3-position of an N-acyl indole will form intramolecular... 

Recently, Fagnou reported a very interesting, atom-economical route to the 1,2,3-trisubstituted indole derivatives 273 via the Rh(II)-catalyzed oxidative coupling-indolization reaction (Scheme 9.95) [251]. Accordingly, simple acetanilides 271, upon a directed C-H activation with the Rh(II)-catalyst [252] followed by a subsequent carborhodation-indolization sequence of alkyne 272, gave N-acylated indoles 273. Both electron-rich and electron-deficient acetanilides 271, possessing different functionalities were perfectly tolerated under these reaction conditions. In the case of unsymmetrical alkyl-alkyl-substituted acetylenes, a mixture of indole products... 

Directed oxidation of N-acyl indoles to the indoxyl system is brought about by the reagent M0O5-HMPT [156], for example ... 

Song, Li, and coworkers reported a Rh-catalyzed oxidative coupling of acrylamides with allcynes to generate 2-pyridones 100 (Eq. (5.97)) [50a]. Both diaryl-or aryl- and alkyl-substituted alkynes were suitable coupling partners for this reaction. The nature of the substituents plays a vital role in this reaction. When the steric hindrance around the olefin or Af-substituent was increased, the reaction afforded N-acyl-indoles as the annulation products. Similarly, Hyster and Rovis reported an improved method for Rh-catalyzed highly regioselective synthesis of pyridones from the annulation of acrylamides and unsymmetrical alkynes [50b]. 

Very recently, Padwa reported a total synthesis of strychnine based on an intramolecular Diels-Alder reaction/rearrangement cascade, which was previously developed in his group to assemble the tetracyclic core ring system of indole alkaloids (Scheme 16) (174-178). Intramolecular cycloaddition reactions often benefit from higher reactivity and greater control of stereoselectivity relative to their intermolecular counterparts. Unlike Bodwell s lEDDA reaction (Scheme 13), the reaction of an electron-rich furan moiety with an N-acyl indole moiety required only a single tether. His synthesis also involved... 

A mild and effective method for obtaining N- acyl- and N- alkyl-pyrroles and -indoles is to carry out these reactions under phase-transfer conditions (80JOC3172). For example, A-benzenesulfonylpyrrole is best prepared from pyrrole under phase-transfer conditions rather than by intermediate generation of the potassium salt (81TL4901). In this case the softer nature of the tetraalkylammonium cation facilitates reaction on nitrogen. The thallium salts of indoles prepared by reaction with thallium(I) ethoxide, a benzene-soluble liquid. 

The modification of the Madelung indole synthesis achieved by introduction of an electron withdrawing group (EWG) at the benzylic carbon atom of the N-acylated-o-alkylanilines has been quite successful. Orlemans et al. reported that indoles were isolated in decent yields when the amides were treated with t-BuOK in THF for a period of 10 minutes at room temperature. ... 

Bischler-Napieralski reactions of N-acyl tryptamine derivatives 16 are believed to proceed via a related mechanism involving the initial formation of intermediate spiroindolenines (17) that rearrange to the observed 2-carboline products (18). The presence of these intermediates has been inferred by the observation of dimerized products that are presumably formed by the intermolecular trapping of the spiroindolenine by unreacted indole present in the reaction mixture." ... 

Acetyl-3-(perhydropyrido[l, 2-u]pyrazin-2-yl)-1 //-indole was deacety-lated in boiling MeOH in the presence of NaOH, and the product, 3-(perhydropyrido[l,2-u]pyrazin-2-yl)-l//-indole was N-acylated with different arylsulfonyl chloride in THF at 0°C in the presence of (Me3Si)2NNa (99MIP12, 01USP6251893)). 

For a general, simple high yield indole synthesis from anilines and methylthioacetaldehyde etc. see JACS 95,588,591,2718,6508 (1973). For indoles from N-( /3 -hydroxy-ethyl aniline esters see BSC 2485(1973). For a 2-acyl-indoles in one step from orthoamino-ketones and alpha-haloketones or 2-carboxyindoles from sulfonamides of ortho-aminocarbonyls see JOC 38,3622-24(1972). Indole and 5-Br-indole in 4 steps from beta-naphthol see Chem. Het. Cpds. (Russ.) 753(1973). Indole-JOC 37,3622(1972). 

This strategy was applied to the total synthesis of ( )-cis- and ( )-trans-trikentrin A [159]. Treatment of 194 with acetic anhydride at 160 °C provided indole derivatives via an N-acylation-[4 + 2]-cycloaddition cascade. Deacylation afforded trikentrin A. 

Bennasar et al. reported a new radical-based route for the synthesis of calothrixin B (378) (869). This synthesis starts from the 2,3-disubstituted N-Boc indole 1558 and uses a regioselective intramolecular acylation of a quinoline ring as the key step for the construction of the calothrixin pentacyclic framework. Chemoselective reaction of in s/fM-generated 3-lithio-2-bromoquinoline [from 2-bromoquinoline 1559 with LDA] with the 3-formylindole 1558 followed by triethylsilane reduction of the... 

Subsequently, the research groups of Terada and AntiUa reported highly enan-tioselective Friedel-Crafts reactions between N-substituted indoles and N-acyl aryl imines (Scheme 5.9) [17]. Interestingly, Antilla states that under his reaction condi-... 

In the acetylation of carbazole using dimethylacetamide-phosgene in methylene chloride, attack was shown to occur mainly at nitrogen (93 7, N C-3) trifluoroacetylation proceeded exclusively at nitrogen. Carbazole was more reactive in this sense than indole and much more reactive than pyrrole, a result paralleling their respective basicities at nitrogen (see Section II,A,3). N-Acylation under these conditions is thought to involve... 

Hidai and co-workers found that 3-vinylindole 326 undergoes cyclocarbonylation to afford 1-acetoxycarbazole 327 [425]. The reaction of indole with allene and CO in the presence of catalytic Pd(0) leads to N-acylation (328) in good yield [426]. An analogous reaction with 5-hydroxyindole affords N- and O-acylation products (47% yield). 

Heterocycles containing an NH group, such as pyrroles, indoles, imidazoles, triazoles, etc., can be linked to insoluble supports as N-alkyl, N-aryl, or N-acyl derivatives (Table 3.29). The optimal choice depends mainly on the NH acidity of the heterocycle in question. Increasing acidity will facilitate the acidolytic cleavage of N-benzyl groups and the nucleophilic cleavage of /V-acyl groups from these heterocycles. 

N-Acylation of indole.1 Indole can be N-acylated by a carboxylic acid in the presence of boric acid (0.3 equiv.) in 45-80% yield. 

N-Acylation was accomplished, for example, with indoles 117 and 316 (72BCJ226 75BCJ314) acyl derivatives are cleaved by alkali or acid... 

In the worst case, there is no such simple distinction between the two sites for enamine formation and we must rely on other methods of control. The nonsteroidal anti-inflammatory drug indomethacin is a good example. Removing the N-acyl group reveals an indole with substituents in both halves of the molecule. 

However, Grignard derivatives of pyrroles and indoles can be used for N-substitution, e.g., Scheme 4 <2004T1197> using the two equivalents of the pyrrolyl Grignard reagent, and at 100 C, gives the C(2)-acylated product 36 via N-acylation then C(2)-metallation and C-acylation. 

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