Nitrones reactions with indoles

Addition of Indoles Pictet-Spengler intramolecular reaction of nitrones (419), synthesized from A -hydroxytryptamine with aldehydes, gave the... 

The reaction of nitrones with indoles in the presence of HC1 gives indolyl N-hydroxylamines. In the presence of Me SiCl symmetrical diindolylalkanes are formed (Scheme 2.193) (679, 680). 

Nitrone cycloaddition reactions with alkynes have been widely used for the synthesis of imidazolidine nitroxides (736) and (737), containing chelating enam-ino ketone groups (821). Different heterocyclic systems were obtained, such as 3-(2-oxygenated alkyl)piperazin-2-ones (738) (822), also compounds containing the isoxazolo[3,2-i]indole ring system (739) (823) and a new class of ene-hydroxylamino ketones- (l )-2-( 1-hydroxy-4,4,5,5-tetraalkylimidazolidin-2-ylidene)ethanones (740) (824) (Fig. 2.46). 

Depending on the nature of the substituents X1, X2, and X3, the reactions produced nitrones (148) (as indole derivatives) or annelated isoxazolines (149). The authors performed a series of experiments (including one with the use of a deuterium label) and suggested a mechanistic scheme for the interpretation... 

The reactions of nitrones with indoles have been applied to die formation of several A -hydroxylamines and symmetrical and unsymmetrical diindolylalkanes.56 Chiral auxiliaries, alcohols derived from (15)-(—)-/ -pinene (R OH), lead to an enantio-selective synthesis when R acetoacetate reacts with 3-(2-hydroxyethyl)mdole in the presence of, for example, BF3.Et20, forming (27).57 Methyl migration follows Friedel-Crafts reaction of (CH3)3SiCCl3 with benzene in the present of A1C13 and (28) is formed.58... 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

An intramolecular cycloaddition reaction is also a vital feature of Oppolzer s synthesis (Scheme 5).336 Here the cycloaddition reaction occurs on an unsaturated nitrone ester (39) (not isolated). Again, the aldehyde derived from oxidation of the diol (40) gave entirely the ( )-olefin on reaction with crystalline a-methoxy-carbonylethylidenetriphenylphosphorane, which allowed the synthesis of (+)-chanoclavine I (34) to be completed in an overall yield of 14% from indole-4-aldehyde. In contrast, the Horner-Emmons reaction on the aldehyde from... 

Aromatic nitro-compounds can be made to condense with silyl-enol-ethers using tris(dimethylamino) sulfur (trimethylsilyl)difluoride (TASF) a non-aromatic nitronate intermediate is aromatised by reaction with bromine, without isolation, to provide a 2-(orf/to-nitroaryl)-ketone and thence an indole after nitro group reduction. ... 

In fight of the successful methodology used by Young and Kerr in the ability of activated cyclopropanes to undergo nucleophilic ring-opening/cycloaddition reactions with indoles and nitrones [21], Johnson and coworkers reported the synthesis of tetrahydrofurans via an adaptation of this... 

Amines. Reaction of PCI3 with quaternary ammonium salts yields phosphaindolizines and thiazolodiazaphospholes. Imines produce phosphonates whereas hydrazones are converted to pyrazoles, indoles, and nitriles. Nitrones undergo rearrangement to secondary or tertiary amides and primary alkylnitro compounds are reduced to nitriles (eq 3). Diazonium salts are transformed to phosphonic acids. ... 

The cyclisation of nitrones derived from tryptamines is a similar process and can be carried out enanti-oselectively using a chiral Lewis acid."° A similar enantioselective intermolecular process is the copper-catalysed reaction of indoles with tosyl-imines of aromatic aldehydes. "... 

There is one more way for conversion of ort/to-nitroarylacetonitriles into indoles. Alkylation of such nitriles with allyl or benzyl halides followed by treatment of the compounds obtained with basic agents results in a multistep transformation, which is likely to proceed via intermediate nitrosoarenes, to produce 1-hydroxyindoles. For instance, alkylation of ort/io-nitroarylacetonitriles with 3-phenylallyl bromide gives the compounds that in the presence of chlorotri-methylsilane and triethylamine undergo cyclization into 3-cyano-l-hydroxy-2-vinylindoles (Scheme 70) [188]. Presumably, this reaction proceeds via 0-silylation of the nitronate anion and 1,5-elimination of trimethylsilanol from the intermediate trimethylsilyl nitronate, followed by cyclization and a hydrogen shift. 

The authors have found that nitronates 11 are derived from intramolecular nucleophilic displacement of the chloro atom with oxygen of the nitro group (Scheme 9). Moreover, the intramolecular VNS reactions of nitroarenes proved to be a successful procedure for the synthesis of various indole derivatives. For instance, cyclization of 3-nitrochloroacetanilide 12 caused by action of f-BuOK affords N-substituted oxindole 13, which is hardly accessible by other methods [28] (Scheme 10). 

Silyl enol ethers and ketene silyl acetals add to aromatic nitro compounds in the presence of TASF(Me) to give intermediate dihydro aromatic nitronates which can be oxidized with bromine or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone to give a-nitroaryl carbonyl compounds the latter are precursors for indoles and oxindoles. The reaction is widely applicable to alkyl-, halo-, and alkoxy-substituted aromatic nitro confounds, including heterocyclic and polynuclear derivatives (eq 7). 

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