Isoindoline 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 method illustrates the ability of the sodium hydride-dimethylformamide system to effect the alkylation of aromatic sulfonamides under mild conditions and in good yield. The method appears to be fairly general. The submitters have prepared N,N-diethyl- and N,N-di- -butyl- >-toluenesulfonamide as well as 2-(/ -tolyIsuIfonyl)benz[/]isoindoline from 2,3-bis-(bromomethyl)naphthalene, and 1 %-tolylsulfony])pyrrolidine from 1,4-dichIorobutane the yield of purified product exceeded 75% in each case. 

Other uses include azo and isoindoline dyes (73GEP2304285 89EUP322359) and long-chained alkyl TP-carboxylates for metal extraction (86FRP2574432). 

Cobalt(III)-alkyl peroxide complexes with the formula Co(BPI)(OOR)(OCOR ) (205 BPI = l,3-bis(2 -pyridylimino)isoindoline R= Bu , CMe2Ph R = Me, Ph, Bu ) have been prepared from the oxidation of Con(BPI)(OCOR ) complexes by alkyl hydroperoxides. The X-ray crystal structure of complex (205) (R=Bu R = Ph) revealed a distorted octahedral environment, with a monodendate OOBuc group and a bidendate carboxylate.635... 

Secondary amines react with 2-ethoxy-4-isopropyloxazoline and acid to give oxazoline derivatives which may also be deprotonated. High enantiomeric excess is possible during alkylation by using chiral oxazolines, as in the preparation of (-t-)-salsolidine (equation 33). Likewise, isoindoline also has been alkylated by using a similar approach. ... 

The following discussion is organized according to the type of heterocycle being alkylated, as follows dehydropyrrolines and isoindolines, followed by dehydropiperidines, tetrahydroisoquinolines and 3-car-bolines. As mentioned previously, the alkylation of saturated heterocycles (the acidic protons being neither allylic nor benzylic) is problematic. Either they fail to metalate when the nitrogen contains a... 

An oxazoline auxiliary has been used to alkylate stereoselectively and regioselectively isoindoline at the a- and a -positions to produce the C2-symmetric amine (12), as shown in Scheme 23. ... 

All other cross-couplings involving terminal alkynes and halo amides have involved ring closure on nitrogen. Thus, o-halobenzamides react with simple terminal alkynes in the presence of a Pd/Cu catalyst to afford either (Z)-3-aryl(alkyl)idene isoindolin-l-ones or the corresponding 2-(l-alkynyl)benza-mides, which are readily cyclized by NaOEt/EtOH or Pd(OAc)2 catalyst to give isoindolin-l-ones (Eq. 11) [35,36]. When acetylenic aryl carbinols are employed as the alkynes, 3-(acylmethyl)isoindolin-l-ones are obtained instead (Eq.l2) [37]. 

Amides, carbamates, and ureas are rapidly alkylated, usually on carbonyl oxygen (see the section on ambident nucleophiles). Alkylation of amides with MeOTSf in CH2CI2 followed by reduction of the salts provides a route for the selective reduction of amides esters, nitriles, acetals, and double bonds are left unaffected by this procedure. Alkylation of isoindolin-l-ones and subsequent deprotonation can provide routes to methoxyisoindoles. ... 

The formation of Af-alkyl isoindolin-l-one through the carbonyiative C-H activation of Af-alkyl benzaldimines with cobalt as the catalyst was achieved by Sen and coworkers in 2006 (Table 15.2) [7]. The author wants to exploit the formation of polypeptides from aldimines with CO after the analysis of the products with GCMS, NMR, and X-ray, it turns out to be the isoindolin-l-one scaffolds. Reactions run under high temperature and pressure (100 °C and 69 bar of CO), and deuterium experiments indicate that the [Co]-H species was generated by the C-H metalation step of the aromatic ring, followed by the insertion to the C=N bond of the benzaldimine affording the final products. 

Phosphoric acid 25a was successfully employed for mediating enantioselective synthesis of 1,3-disubstituted isoindolines from electrophilic bifunctional substrates (containing an imine and a Michael acceptor site) and indoles [33]. Catalyst 7a was used effectively in an organocatalytic asymmetric F-C alkylation/cyclization cascade reaction between 1-naphthols and a,(i-unsaturated aldehydes to give chro-manes in good yields and select vities (Scheme 3 5.18) [ 10]. Furthermore, 2-naphthols and p,y-unsaturated a-keto ester also reacted in a F-C alkylation/dehydration sequence, in the presence of a thiourea catalyst and a catalytic amount of concentrated sulfuric acid, affording optically active naphthopyran derivatives [54]. 

The ehiral phosphoiie aeid (i )-(231) has been shown as an efficient Bronsted aeid eatalyst in asymmetrie synthesis of various acyclic and endo exocyclic p-hydroxyenones (230) through a regiospecific aldol condensation between a,p- unsaturated ketones (228) and ethyl glyoxalate (229) (Seheme 60). Enantioseleetive synthesis of 3-indolyl-substituted isoindolin-l-ones (234) through the ehiral phosphoric add (235) catalysed asymmetric Friedel-Crafts alkylation of indoles (232) with 3-hydroxyisoindolin-l-ones (233) in excellent ehemieal yields (up to 99%) and with moderate to good enantioselectivities (up to 99% ee), has been described by Zhou et al. (Scheme 61). ... 

The same authors used the chiral phosphoric acid (300) in enantioselective asymmetric Friedel-Crafts alkylation reaction of indoles (324) with 3-sub-stituted 3-hydroxyisoindolin-l-ones (325) in synthesising 3,3-disubstituted isoindolin-l-ones (326), in excellent chemical yields (up to 99%) and with good to excellent enantioselectivities (up to 95% ee) (Scheme 85). ... 

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