Isoindoles alkylation

Elimination from A -oxides of substituted isoindolines provides an exceptionally facile synthesis of the isoindole sy.stem. Kreher and Seubert found that treatment of the oxides of both 2-alkyl- and 2-arylisoindolines with acetic anhydride at 0° to —10° afforded... 

The intermediate alkylation product (33) undergoes facile elimination. In one instance a hydroxyisoindoline (34) was isolated and subsequently dehydrated to the corresponding isoindole.The phthal-imidine route has been used to prepare mainly 1,2-disubstitutcd... 

Isoindole itself gives normal Diels-Alder addition products, (107 and 108), with maleic anhydride and A-phcnylmaleimide, these derivatives constituting the main evidence for forma,tion of the parent substance. 2-Alkyl- and 2-arylisoindoles also give normal addition products with these two dienophiles.Although only one product is generally isolated, it seems likely, in view of the known tendency of several Diels-Alder adducts of isoindoles to dissociate to their components (see below), that both exo and endo stereoisomers might be formed in certain cases. The reaction between 2-p-tolyl-isoindole and A-phenylmaleimide has been shown to give both e,xo (109) and endo (110) addition products. ... 

Accurate, quantitative spectroscopic data for the simple alkyl-substituted derivatives of isoindole are not available, cither because of their inherent instability or tendency to tautomerize to isoindole-nines. However, the presence of an isoindole in a tautomeric mixture can be readily discerned by means of ultraviolet spectroscopy. ... 

The mesomeric effect of the C=S linkage is very pronounced and is responsible for the facile quaternization of heterocyclic N-alkylated thiones (159) this effect is operative even when such a shift does not increase the aromaticity of the ring. Thione derivatives of pyridazine, benzothiazole, quinazoline, 1,3-thiazine, triazole,and isoindole are examples of compounds which readily form quaternary salts. 

Isoindole has been isolated only in the C-alkyl form [173] (Bender and Bonnett, 1966). Nmr spectra show that its protonation... 

Isoindole is an interesting precursor for successive alkylations at the a- and a -positions because both are benzylic. Oxazoline ° and formamidine auxiliaries have been used to accomplish the a,a -dialkylation to give a C2-symmetric amine. The C2-symmetric amine products are envisioned as possible tools for a variety of asymmetric processes. The diastereoselectivity of the second alkylation is enhanced by the presence of the stereocenter formed in the first alkylation (Scheme 61). ° Several other electrophiles were evaluated with the formamidine auxiliary. ... 

The enolates derived from racemic 2-(trimethylsiIyI)- or 2-benzyl-3-ethoxy-2,3,3a<4,7,7a-hexa-hydro-1 //-isoindol-l-one (13) react with some haloalkynes. Attack by the electrophile occurs at the bridgehead carbon (7a) from the least hindered side, to afford only one diastereomer of the alkylation product 14, as judged by spectroscopic properties14,15. In some experiments 2-desilylation is effected before product isolation15. 

When treated with lithium diisopropylamide at low temperature, t-ac-2,3-dibenzyl-octahydro-1 //-isoindol-l-one (19) yields the enolate. Alkylation with iodomethane then proceeds from the least hindered side to give only one diastereomer 20 in 57% yield17. 

Alkylation of isoindoles at the 1- or 3-positions under Mannich reaction conditions has also been reported, although the presence of a strong electron-withdrawing substituent at the 1-position inhibits the reaction (81AHC(29)34l). 

The introduction of alkyl groups on pyrroles, indoles, isoindoles and carbazoles can usefully be subdivided according to the desired locus of substitution. There are three distinct... 

Alkylation of carbazole has not been studied systematically but isolated preparative examples suggest that N- alkylation can be carried out as for pyrroles and indoles. No complication from competing carbon alkylation occurs. N- Alkylation of the anion of isoindole does not seem to have been investigated. One might expect serious competition from C- alkylation because of the favorable benzenoid conjugation of the resonance structure with charge on carbon (equation 161). 

This microwave-accelerated double alkylation reaction was applicable to a variety of aniline derivatives and dihalides, furnishing N-aryl azacycloalkanes in good to excellent yields [89]. The reaction was applicable to alkyl chlorides, bromides and iodides and was extended to include hydrazines [90]. This improved synthetic methodology provided a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted-2,3-dihydro-Iff-isoindoles, 4,5-dihydro-pyrazoles, pyrazolidines, and 1,2-dihydro-phthalazines [91]. The mild reaction conditions tolerated a variety of functional groups such as hydroxyls, carbonyls, and esters. 

The reaction of aromatic orf/zo-substituted imidoyllithiums 56 with carbon monoxide and methyl iodide afforded li/-isoindole derivatives 61 in moderate yields (Scheme 16)77. In this process the formation of an acyllithium 57 was proposed to occur which, after formation of intermediate 58, cyclized to give the compound 59. The rearrangement of the alkyl group giving the aromatic product 60, followed by quenching with methyl iodide at — 78 °C, gave indolines 61. 

A cascade approach to isoindole-1-phosphonates 9 starting from from o-alkynyl benzylamides was reported <07OL465>. The cascade sequence presumably involved a 5-exo-dig cyclization, a [1,3]-alkyl shift (or aza-Claisen), and aromatization. 

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