Indole derivatives 3- acylation

Another substrate class, for which the outcomes of a radical and a carbocationic process are opposite, are indoles (Fig. 85) [418], Indeed, when oxaziridines 315a or 315c were treated with indoles 314c in the presence of 2 or 10 mol% of C11CI2/ TBAC oxazolidinoindolines 316c were obtained as the exclusive products in 53-90% yield. The reaction is applicable to 2-, 3-, and 2,3-disubstituted indoles. Chiral indole derivatives acylated with (S)-proline units at nitrogen underwent asymmetric diastereoselective aminohydroxylation reactions with 86-91% de. Tricyclic hemiaminals derived from tryptamine derivatives could be transformed to pyrrolidinoindolines, which are core structures of a number of alkaloids. 

The unexpected formation of cyclopenta[b]indole 3-339 and cyclohepta[b]indole derivatives has been observed by Bennasar and coworkers when a mixture of 2-in-dolylselenoester 3-333 and different alkene acceptors (e. g., 3-335) was subjected to nonreductive radical conditions (hexabutylditin, benzene, irradiation or TTMSS, AIBN) [132]. The process can be explained by considering the initial formation of acyl radical 3-334, which carries out an intermolecular radical addition onto the alkene 3-335, generating intermediate 3-336 (Scheme 3.81). Subsequent 5-erafo-trig cyclization leads to the formation of indoline radical 3-337, which finally is oxidized via an unknown mechanism (the involvement of AIBN with 3-338 as intermediate is proposed) to give the indole derivative 3-339. 

Yoshino reports a novel and general method for the C-3 acylation of indoles with acyl chlorides in the presence of dialkylaluminium chloride which obviates the need for prior N-protection . Interestingly, as described in this preliminary communication, the unprotected indoles 147 are first treated with the Lewis acids prior to addition of the acid chlorides, yielding the desired 3-acyl derivatives 148. In reactions more typical of indoles under acidic conditions, Nakatsuka determined the structures of the dimers and trimers of 1-trimethylacetylindole produced in the presence of aluminium chloride . 

TV-Acyl indoles derived from amides have been employed for the conversion of lactones into protected hydroxyacids. Thus, (chloromethyl)alumi-num 2-(2-propenyl)anilide reacts (120) with 1,4- and 1,5-lactones, as for example per-O-terZ-butyldimethylsilyl-D-ribono-1,4-lactone (104), to afford hydroxyamides. After protection of the free hydroxyl group, these amides were converted by ozonolysis into TV-acyl indoles, 105, which were readily saponified to the acid 106. 

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. 

Gonzalez and Galvez269 have described an improved method for the preparation of 3-diazoindoles (174), using PTC. Indole derivatives 173 react in position 3 because of the ambident reactivity of the molecule. Yields are 75-90% when R is acyl or heteroaryl. 

Generation of 3-indolylacyl radicals from the selenoesters 149, using either /j-Bu3SnH or tris(trimethylsilyl)silane (TTMSS) followed by reaction with various alkenes, offers a route to 3-acylindoles 150. On the other hand, the use of n-Bu Sn2 under irradiation gave cyclopent[6]indole derivatives such as 151 via a cascade involving initial addition of the acyl radical to the alkene, and a subsequent oxidative cyclization at the indole C-2 <02JOC6268>. 

When intermediate 81 is formed from indole 80 and l,l -carbonyldiimidazole (GDI) using DMAP to promote indole nitrogen acylation in acetonitrile at reflux, it is reasonably stable, observed by TLC, but not isolated. Treatment of intermediate 81 in situ with amines, alcohols, or thiols afforded the desired derivatives 82. During the reaction of indoles with GDI, some carbonyl diindole 83 was formed. In many cases this material could be isolated and characterized. In an alternative approach, alcohols reacted with GDI stoichiometrically to form an unstable intermediate carbamate species 84, which could in turn be reacted with indoles to form the desired indole-1-carboxylates 82. This new methodology for the formation of compound 82 proved to be useful in one of the approaches for the synthesis of novel Serotonergics. 

Thermal decomposition of phenyliodonium ylide of 2-hydroxy-l,4-naphthoquinone (lawsone) 403 in the presence of indole derivatives 402 (GH2CI2, reflux, 4-7 h) affords 3-acylated indoles existing in their enol forms 404, through a ring contraction and ot,ot -dioxoketene formation reaction (Scheme 87) <2005JOC8780>. 

Although considered mild in comparison with other metals, copper(I) and (II) Inflates are suitable Lewis acids for affecting Friedel-Crafts alkylation and acylation reactions (Sch. 22). The intramolecular acylaminoalkylation of the indole derivative 88 afforded the cyclized product 89 in high yield [49]. The nitrogen functionality was not a requirement for formation of the benzylic cation, because the benzylic alcohol 90 reacted similarly with 91, even with an electron-withdrawing ester group adjacent to the cationic center. 

Substituted 2-(morpholinocarbonyl)-6-(trifluoromethyl)furo[3,2-Z)]indole derivatives (341) have been obtained by the reaction of (340) with acyl chlorides, alkyl halides and alkenyl halides under basic conditions (Equation (7)) <86JMC2284>. 

An interesting approach to arylacetaldehydes involves vinylene carbonate as a reactant. With W-acyl-2-iodoanilines, the products are the W-protected 2-hydroxyindolines, which are readily dehydrated to give the corresponding indole derivatives. 3-Acyloxy-3-buten-2-ones undergo fZ)-selective arylation at C-4. ... 

The regiochemical course of the above reactions was similar to what was observed in Pindur s work. However, the diastereoselectivity for the Diels-Alder reactions involving A-acylated indoles 139 was quite different than that previously reported. When the unprotected indole derivatives 135 were subjected to Diels-Alder cycloadditions, the endo products were formed almost exclusively. In contrast, the cycloadditions with A-protected indoles in the presence of magnesium perchlorate as the Lewis acid provided a wide range of endo/exo product ratios (143 144, Scheme 36). 

Historically, Friedel-Crafts acylations of N-unsubstituted indoles were found to provide a mixture of 3-acyl- and 1,3-diacylindoles. Last year, Yoshino disclosed a novel method for the regioselective C-3 acylation of N-unsubstituted indoles with acyl chlorides in the presence of dialkylaluminum chlorides in a process that obviated the need for prior N-protection . Intriguingly, despite the known susceptibility of ind(jles towards acid-catalyzed dimerization processes, Yoshino nevertheless pretreated the indoles 166 with the Lewis acid prior to addition of the acid chlorides, an artifice that in some way may account for the observed selectivity for the desired 3-acyl derivatives J67. Ottoni confirms the effectiveness of this sequence and also notes the importance of added nitromethane as cosolvent <010L1005>. 

Aminoalkylindoles are generally synthesized by following either Method A or Method B as depicted in Scheme 12(65,66). An appropriately functionalized indole was aroylated in the first step followed by A-alkylation (Method A). Alternatively, A-alkylation could be accomplished first, followed by aroylation of the resulting indole derivative at C3 (Method B). For acid-sensitive analogs, EtAlCl2 is used in place of AICI3 in Friedel-Crafts acylation. 

The enantioselective Friedel-Crafts reaction of a. unsaturated 2-acyl iV-methylimidazoles with electron-rich heterocycles, such as indole derivatives, 2-methoxyfuran, and pyrrole, was catalyzed by Sc(OTf)3 conjointly used with a chiral bis(oxazolinyl)pytidine ligand (eq 31). The reaction afforded good enantioselectivities (>90% ee) for a broad range of substrates. 

This reaction has been extended to the translocation of the acyl group for indole derivatives. In addition, a chiral planar DMAP derivative has been developed and applied for the enantioselective rearrangement of 0-acylated azlactone and the same catalyst recently has been used for an intermolecular reaction to form 1,3-diketones. Moreover, 3-(2,2,2-triphenyl-1 -acetoxyethyl)-4-(dimethylamino) pyridine (TADMAP) has been applied as a chiral nucleophilic catalyst to catalyze the carboxyl migration of oxazolyl, furanyl, and benzofuranyl enol carbonates with good to excellent levels of enantioselec-tivity. The rearrangement for oxazole derivatives are particularly efficient for giving chiral lactams and lactones. ... 

This success was now further extended to the indole derivatives by replacing a dimethoxybenzene ring to an indole ring. Thus it was suggested that photocyclization of enamides prepared from harma-lane by acylation with 2- or 3-furoyl chloride would provide a novel synthesis of the biologically useful alkaloid ajmalicine and the hitherto untouched alkaloid hirsuteine. This synthetic strategy was just an another extension of the above emetine synthesis as shown in the scheme. 

Ganesan et al. reported the total synthesis of the cell cycle inhibitor (-)-spirotryprostatin B (622) in 2000 (411). Their synthesis started with L-tryptophan methyl ester 616, which was treated with senecialdehyde to give imine 617. The indole derivative reacted in a iV-acyl-iminium Pictet-Spengler condensation to yield the tetrahydro-p-carboline derivative 618 (412) (Scheme 10.2). 

Isatins are indole derivatives with broad use in synthetic dye production and are intermediates in the synthesis of other heterocyclic molecules/ They also possess a variety of biological activities/ Aksenov et al. reported a one-pot synthesis of isatins using ethyl nitroacetate with substituted benzenes such as anisole (159) in polyphosphoric acid fScheme 5.38)/ The process for isatin formation likely includes a hybrid between the Nef and Vilsmeier reactions of anisole 159 and nitro ester 160 to form the oxime intermediate 161, which then undergoes a Beckmann rearrangement to give the anilide 162. Subsequent intramolecular acylation yields isatin 163. 

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... 

Indole-fused pyran-4-ones are prepared in one-pot two-step synthesis. In the first there is the acylation of 1-substituted 3-acetyl-lH-indol-2-ols with acid chlorides using triethylamine as base, in dichloromethane at room temperature. The second consists in the 4ff-pyran-4-one ring formation firom the in situ-obtained 3-acetyl-2-acyloxy-lF/-indole derivatives (13S1235).A highly diastereo- and enantioselective organocatalytic formal hDA reaction of enones with isatins occurs in the presence of amine 34, acid 35, and thiourea 36 to produce spirooxindole tetrahydro-4ff-pyran-4-ones (Scheme 59) (13CEJ6213). 

Enantioselective Friedel-Crafts alkylation of indoles with a,P-unsaturated acyl phosphonates was investigated in the presence of bis(oxazolinyl)pyridine-scandium triflate complexes [151]. The intermediate -indolyl acyl phosphonates were converted to the corresponding methyl esters by direct addition of methanol and DBU (1,8-diazobicyclo [5.4.0] undec-7-ene) to the reaction mixture. Various acyl phosphonates and indole derivatives gave the alkylated products in moderate to good yields with high to excellent enantioselectivities (Scheme 12.57). It was also shown that the reaction was quenched by morpholine to give the corresponding amide, and that electron-rich 3-dimethylaminoanisole was also an effective nucleophile in this reaction. 

Later, this catalytic system was successfully applied to the Friedel-Crafts alkylation of various a,P-unsaturated 2-acyl imidazoles with indole derivatives [152]. The corresponding products were obtained in moderate to excellent yields with moderate to excellent enantioselectivities, the best selectivity being displayed with... 

---