Reactivity and regioselectivity in the synthesis of spiroindoles via indole o-quinodimethanes. An experimental and computational study

The 1,3-dipolar cycloaddition reactions of stable nitrile oxides with indole o-quinodimethanes have been examined. In all cases the ‘exo-anti’ addition products, dispiroisoxazolines, were isolated in moderate to good yields (25-47%). In addition, from the reaction of one of the indole quinodimethanes with mesitonitrile oxide the ‘exo-syn’ addition product was isolated in 7% yield along with the remarkable indole quinodimethane dimerization and cycloaddition product, which was isolated in 13% yield. An analogous dimerization and cycloaddition product was isolated in 18% yield from the reaction of the N-acetyl-indole quinodimethane with mesitonitrile oxide. In the case of the reaction of the N-benzoylindole quinodimethane with the 2,6-dichlorobenzonitrile oxide an oxime was also isolated in 13% yield. The proposed reaction mechanism is supported by semiempirical (AM1) MO calculations via FMO interactions. The observed selectivity was explained by an investigation of the transition states carried out also for analogous dispiroisoxazolines.     

The first application of an imidazole o-quinodimethane in Diels-Alder reactions leading to the synthesis of benzimidazoles

An efficient procedure for the generation of the imidazole-4,5-quinodimethane intermediate 4 from 2-bromo-4,5-bis(bromomethyl)imidazole derivative 3 in boiling toluene in the presence of 18-crown-6 is described. o-Quinodimethane 4 was captured for the first time by several symmetrically and unsymmetrically substituted dienophiles to afford the corresponding Diels-Alder benzimidazole adducts.     

Facile preparation of bicyclo[2.2.2]octenone derivatives via Diels-Alder cycloadditions of in situ-generated masked o-benzoquinones

Diels-Alder cycloadditions of in situ-generated, substituted 2,2-dimethoxycyclohexa-3,5-dienones with olefinic dienophiles resulted in the development of an efficient method for the preparation of highly functionalized bicyclo[2.2.2]oct-5-en-2-ones with good to excellent yields.     

Novel porphyrin-quinazoline conjugates via the Diels-Alder reaction

Novel derivatives of meso-tetraphenylporphyrin with appended quinazoline moieties were synthesized, via the Diels-Alder reaction, between a 4-(porphyrinyl)pyrimidine ortho-quinodimethane and 1,4-benzoquinone, 1,4-naphthoquinone and N-(p-nitrophenyl)maleimide. The structure of one bis adduct was established by X-ray crystallography and mass spectrometry. We have unequivocally confirmed that the 2:1 adducts obtained from the reaction of pyrimidine-fused 3-sulfolenes with N-arylmaleimides have an open-chain structure and not a cyclooctapyrimidine structure, as previously published.     

Diels-Alder reactions of masked o-benzoquinones with acrylonitrile

Regioselective Diels-Alder reactions of masked o-benzoquinones (MOBs) 2a-i derived from the corresponding 2-methoxyphenols 1a-i with acrylonitrile leading to highly functionalized bicyclo[2.2.2]octenone derivatives in high yields are described.     

Efficient synthesis of o-alkynyl-N-pivaloylanilines from o-acyl-N-pivaloylanilines and lithium trimethylsilyldiazomethane

Reaction of o-acyl-N-pivaloylanilines with lithium trimethylsilyldiazomethane efficiently gave the corresponding o-alkynyl-N-pivaloylanilines via alkylidenecarbene intermediates.     

Diels-Alder reaction of 4-halogenated masked o-benzoquinones with electron-rich dienophiles

Inverse-electron-demand Diels-Alder reaction of masked o-benzoquinones (MOBs) ensuing from the corresponding 4-halo-2-methoxyphenols with styrene, dihydrofuran and ethyl vinyl ether, butyl vinyl ether, phenyl vinyl sulfide and vinyl acetate to afford the highly functionalized halogen substituted bicylclo[2.2.2]octenones are described.     

Diastereoselective synthesis of β-aminocyclopentene sulfonic acid via hetero Diels-Alder reaction

A new cyclopentene GABA analogue was synthesized as a conformationally rigid analogue of the epilepsy drug vigabatrin. N-Sulfinyl dienophile Diels-Alder methodology, followed by alkaline hydrolysis of the corresponding dihydrothiazine oxide, oxidation and deprotection of the amino group gave cis-4-aminocyclopent-2-ene-1-sulfonic acid. The corresponding N,N-dimethylsulfinamide was also obtained.     

o-Thioquinones on [2.2]paracyclophanes: an example of totally stereocontrolled hetero Diels-Alder reactions

The reaction of 4-hydroxy[2.2]paracyclophane with phthalimidesulfenyl chloride allowed the preparation of a suitable precursor for a paracyclophane-o-thioquinone. This species participates in an inverse electron demand hetero Diels-Alder reaction with different electron-rich alkenes to give the expected benzoxathiin cycloadducts with complete control of regio- and stereochemistry.     

The first benzodiazepine o-quinodimethane: generation and Diels-Alder reactions

7,8-Bis(dibromomethyl)-3-bromo-2,4-diphenyl-3H-benzodiazepine 1 was used as a precursor for the benzodiazepine o-quinodimethane 2, which was trapped by in situ reactions with dienophiles.     

Synthesis of polycyclic pyrazoles through formation of the first fused heterocyclic o-quinodimethane intermediate

1-Benzoyl-4,6-dibromo-3-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (2) was used as a precursor for o-quinodimethane 3, which was trapped by in situ reactions with dienophiles to give bridged pyrazole derivatives.     

Enantioselective organocatalytic aryloxylation of aldehydes with o-quinones

An enantioselective organocatalytic inverse electron demand hetero Diels-Alder reaction of in situ generated enamines with o-quinone reagents is reported. The method, which is optimal in wet acetonitrile at ambient temperature, provides a new and direct asymmetric route to the aryl alkyl ether motif and an alternative metal-free strategy to S_N2 substitutions with phenolate nucleophiles.     

Diastereo- and regioselective Diels-Alder reactions of 2-phosphaindolizines

1,3-Bis(alkoxycarbonyl)-2-phosphaindolizines undergo Diels-Alder reactions at the CP- functionality with 2,3-dimethylbutadiene and with isoprene in the presence of sulfur with complete diastereoselectivity. The reaction with isoprene occurs with 100% regioselectivity as well. 3-Ethoxycarbonyl-1-methyl-2-phosphaindolizine, however, fails to undergo Diels-Alder reaction under these conditions. Difference in the dienophilic reactivities of mono- and bis(alkoxycarbonyl) substituted 2-phosphaindolizines and the observed regioselectivity in the Diels-Alder reaction has been rationalized on the basis of DFT calculations. The relative stabilities of the transition structures have been explained on the basis of the NBO analysis.     

Unique chlorine effect in regioselective one-pot synthesis of 1-alkyl-/allyl-3-(o-chlorobenzyl) uracils: anti-HIV activity of selected uracil derivatives

2,4-Bis(trimethylsilyloxy)pyrimidines 1/2 on reaction with o-chlorobenzyl chlorides in 1,2-dichloroethane in the presence of I₂ undergo single step 1,3-dibenzylation to provide 1,3-bis(o-chlorobenzyl)pyrimidine-2,4-diones. The reactions of 1 with allyl/alkyl bromide followed by subsequent addition of o-chlorobenzyl chloride provide a simple one-pot synthesis of 1,3-unsymmetrical pyrimidine-2,4-diones. Amongst these, 1,3-bis(o-chlorobenzyl)uracil (6a) shows anti-HIV-1 activity.     

A simple method for the oxidation of primary alcohols with o-iodoxybenzoic acid (IBX) in the presence of acetic acid

A simple method for the oxidation of primary alcohols to aldehydes using o-iodoxybenzoic acid (IBX) with the addition of stoichiometric acetic acid has been developed. Addition of acetic acid significantly accelerated the reaction rate. Under these conditions, primary aliphatic, benzylic, and allylic alcohols are smoothly converted to aldehydes in high yields (90-97%).     

Reversal of the regioselectivity in a cycloaddition of o-quinones by varying the position of alkoxy substituents

We have investigated the regioselective cycloaddition of o-quinones 1b-e with the protected sinapyl alcohol 2. It was found that the position of the alkoxy substituent on the o-quinone ring controlled the regioselectivity of the cycloaddition. In addition, our reported procedure for determining the location of the side chains on 1,4-benzodioxanes has been improved.     

One-pot synthesis of benzimidazoles from gem-dibromomethylarenes using o-diaminoarenes

A one-pot synthesis of benzimidazoles from gem-dibromomethylarenes is described. The reaction shows the method to prepare a variety of benzimidazole analogues with excellent yield.     

One-pot approach for the synthesis of 2-aryl benzothiazoles via a two-component coupling of gem-dibromomethylarenes and o-aminothiophenols

One-pot synthesis of 2-aryl benzothiazoles from gem-dibromomethylarenes using 2-aminoarylthiols is described. Benzothiazoles were obtained in high chemical yields under mild conditions. This transformation would facilitate synthesis by short reaction times, large-scale synthesis, easy and quick isolation of the products, which are the main advantages of this procedure.     

Formation of reactive o-quinone methides from the reaction of trimethylsilyl(methyl)-substituted 1,4-benzoquinones with nucleophiles

o-Quinone methides are formed from the reaction of nucleophiles with trimethylsilyl(methyl)-1,4-benzoquinones. These reactive intermediates are trapped by excess nucleophile to form substituted quinones following oxidation. In addition, varying amounts of a symmetrical dimer and a xanthen derivative were observed. The influence of different nucleophiles and ring substituents on the rate of reaction have been studied, and are consistent with rate-limiting formation of a vinylogous enolate initiated by attack of the nucleophile on the silyl group.     

Chromone-3-carboxaldehydes in Diels-Alder reactions with indole-o-quinodimethane. Synthesis of tetrahydrochromeno[2,3-b]carbazoles

An efficient route to a new class of indole derivatives, tetrahydrochromeno[2,3-b]carbazoles, has been developed. The cycloaddition reactions of chromone-3-carboxaldehydes with indole-o-quinodimethane gave a diastereomeric mixture of Diels-Alder cycloadducts in good yields after in situ deformylation.