Indoles with carbonyls

Hasaninejad, A., Zare, A., Sharghi, H., Niknam, K., and Shekouhy, M. 2007. P20j/Si02 as an efficient, mild, and heterogeneous catalytic system for the condensation of indoles with carbonyl compounds under solvent-free conditions. ARKIVOC, (xiv) 39-50. 

Seyedi, N., Khabazzadeh, H. and Saidi, K. 2009. CU15PM012O40 as an efficient, mild and heterogeneous catalyst for the condensation of indole with carbonyl compounds. Mol. Divers. 13(3) 337-342. 

C Control of Indole Polyalkylation Side Reaction in the Asymmetric Alkylation of Indoles with Carbonyl Compounds (Section B. Part 1) and Imines (Subsequent Section B, Part 2)... 

Baran PS, Richter JM (2004) Direct coupling of indoles with carbonyl compounds short, enantioselective, gram-scale synthetic entry into the hapalindole and fischerindole alkaloid families. J Am Chem Soc 126 7450-7451... 

The early literature on the reactions of the indole Grignard reagents with the simple diacid chlorides, in particular with carbonyl chloride and oxalyl chloride (see Section III,C,4,b), is both conflicting and confusing and much of the work reported warrants repetition since the evidence presented in support of many of the structural assignments made is not entirel3 convincing. 

It was unusual to find that both enantiomers had similar activity in vitro, but these are relatively planar molecules in which the asymmetric centre is well separated from the basic end group, so there is close coincidence of the key recognition sites of the indole nucleus, carbonyl function and basic imidazole nitrogen atom. The quaternary derivative (20) of ondansetron retained activity (RVN p 2 8.4), suggesting that the imidazole ring is pro-tonated in the binding interaction with the receptor. 

With an excess of the lithiating agent, 1-benzenesulfonylindoles form dilithiated derivatives, which may be dialkylated or dideuterated (81JHC807). Reaction with carbonyl compounds, however, may result in the formation of the 2-substituted indole with cleavage of the protecting group (Scheme 37), although the reaction with benzoyl chloride yields the sultam (134). 

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. 

Alkyl isocyanides undergo a smooth reaction with isopropylidene Meldrum s acid 396 in the presence of pyrrole or indole to produce 1-alkyl-3,3-dimethyl-4-(l//-pyrrole-2-carbonyl)-pyrrolidine-2,5-diones 400 (Scheme 86) or 1-alkyl-4-(lf/-indole-3-carbonyl)-3,3-dimethyl-pyrrolidine-2,5-diones 401 (Equation 94) in good yields <2004S0989>. 

Reagents of type 251 (Fig. 94) are aldehydes or phosphoranes which, by reaction with kctonic and indolic Mannich bases, allow the production of p-diketones 252 or phosphoranes 253, respectively. In the former case, the conversion of aldehyde to ketone is thus made possible, - - and in the latter, the formation of unsaturated derivatives by subsequent reaction of the PPh3 residue with carbonyl compounds is allowed. - ... 

In the simplest of these, jS-enaminones are synthesized (equation 129) by the addition of amines to 1,3-diketones or /3-ketoesters. The reaction has been apphed to the Friedlander synthesis of quinolines by condensation of the enaminone and other carbonyl present in the substrate. Substituted pyrroles in equation (130) can be obtained as well when a propargyl group is present, by addition of the enaminone to the triple bond. Alcohols, thiols, and secondary phosphines have been also tested as nucleophiles with good results. A particularly interesting case is found in the condensation of indoles with 1,3-diketones to give substituted indol derivatives in equation (131). ... 

Methods involving rntheninm-catalysed condensations of arylamines with alcohols give indoles the mechanism involves hydride transfer giving aldehyde intermediates. The process can be carried ont intra-molecnlarly or intermolecnlarly, for example by the reaction of aniline with triethanolamine. At a still lower oxidation level, 2-(ort/t(9-aminoaryl)-ethanols can be converted directly into indoles with a catalyst that can oxidise the alcohol to a carbonyl gronp, with expulsion of hydrogen. 

Sarhan (01M753) (Scheme 28) condensed lH-indole-3-carboxylic acid hydrazide 120 with ethyl 3-oxobutanoate 5 without solvent and isolated hydrazone 121 in 70% yield. Compound 121 could be cyclized to l-(lH-indole-2-carbonyl)pyrazol-3-one 122 in 67% yield by heating in a mixture of ethanol and acetic acid (10 2 ratio). Using this solvent, mixture pyrazol-3-one 681 was obtained independently in 34% yield by heating hydrazide 120 with ethyl 3-oxobutanoate 5. 

Only one thiophene has been reported to undergo (2 + 2)-cyclo-addition with carbonyl compounds, viz., 2,5-dimethylthiophene.210 In this reaction, too, only one type of isomer (180) was obtained, in 50-60% yield. N-Benzoyl-l//-pyrrole reacted with two molecules of ketone to give cycloadduct 181.211 Similarly, JV-acyl-1//-indoles reacted with certain ketones to produce adducts 182.212 The lack of reactivity of other heterocycles, such as 1//-pyrroles, oxazoles, and isoxazoles, has been attributed to a quenching effect on the excited ketone of the non-bonded electrons on the heteroatom.212... 

Although indoles are less reactive than pyrroles, they react with arenediazonium salts to give 3-(aryl-azo)indoles. The reaction with carbonyl compounds proceeds in an analogous way in the presence of acids. For this reason, indoles unsubstituted in the 3-position give a positive colour test with Ehrlich s reagent. Indole and acetaldehyde react via an azafulvenium salt to give 3-Vinylindole, which on further reaction with indole forms l,l-di(indol-3-yl)ethane ... 

In chromium carbonyl complexes of indole, the metal is associated with the benzene ring, hence nucleophilic additions take place in that ring, usually at C-4 the example shows the relatively unusual attack at C-7 this regioselectivity can be induced to revert to the usual C-4 if an indole with a bulky A-protecting group is utilised. ... 

Procedures for Pd-catalyzed coupling with carbonylation to give 2-acyl indoles were also reported. Triethyl(l-methylindol-2-yl)borate, which can be prepared from 1-methylindole by lithiation followed by addition to triethylborane, was coupled with aryl iodides and vinyl triflates to give 2-acyl indoles in 20-80% yield. <94J0C2634> The reactions were run with PdClj(PPh3)2 as catalyst under 15 atm of CO at 90 . 

The reaction of indole and its alkyl derivatives with carbonyl compounds under acidic conditions usually forms b -(3-indolyl)methanes. 

Samarium diiodide-induced intermolecular coupling of aldehydes and ketones to indoles with an electron-withdrawing group at the 3-position of the indole have also been reported [19]. Carbonyl compounds including acetone, acetophenone, benzophenone, pivaldehyde, and isobutyraldehyde added to the C-2 position of the indole to give the thermodynamically stable trani-dihydroindole derivatives 27. 

In addition to alkenes and acetylenes, carbonyl-containing compounds also participate in [2+2] cycloaddition reactions with indoles. The first example of oxetane formation via the photoreaction of indoles with a carbonyl group (a type of Patemo-Biichi reaction) was reported by Machida and coworkers [34, 35] (Scheme 16), who carried out the intramolecular cyclization of iV-acetylindole with phthalimide tethered with appropriate linkers 67a-d. Interestingly, only the... 

Intramolecular Wittig reactions can be used for the preparation of cyclic alkenes. The formation of the phosphonium ylide must be compatible with other functionality in the molecule and thus stabilized ylides are used most commonly. Wittig reactions with carbonyl groups other than aldehydes or ketones, such as carboxylic esters, are known. For example, a route to the indole or penem ring systems uses a carboxylic amide or a thioester respectively as the intramolecular electrophile (2.77). 

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