Isocyanides are exceptional building blocks whose wide deployment in multi-component and metal insertion reactions belies their limited availability. Addressing this deficiency is the first conjugate addition-alkylation method. An array of organolithiums, magnesiates, enolates, and metalated nitriles, add conjugately to β- and β, β-disubstituted arylsulfonyl alkenyl isocyanides to rapidly assemble diverse isocyanide scaffolds. The intermediate metalated isocyanides are efficiently trapped with electrophiles to generate substituted isocyanides incorporating contiguous tri- and tetra-substituted centers. The substituted isocyanides are ideally functionalized for elaboration into synthetic targets as illustrated by the three-step synthesis of the γ-carboline, N-methyl ingenine B.

Keywords: arylaminofumarates, maleimide, pyrrole-2,5-dione, transamination.3-Arylaminopyrrole-2,5-dione derivatives show fungistatic [1], herbicidal, insecticidal [2], and antitumor activity [3] and are used for the treatment and/or prophylaxis of cancer as well as conditions needing inhibition of the enzyme GSK-3 (diabetes, Alzheimer disease, and acute stroke) [4].The synthesis of 3-arylaminopyrrole-2,5-diones and their 1-alkyl derivatives is based on the cyclization of arylaminofumarates with ammonia [5], treatment of maleimides with arylhydroxylamines [6], or on the reaction of 3-halo- [4,5,7,8] or 3-hydroxy-[4, 8] pyrrole-2,5-diones with arylamines. It is also known that enamines are transaminated by amines under conditions of acid or base catalysis: 1,4-bis(dimethylamino)-1,3-butadiene by aryl and alkylamines in the presence of catalytic amounts of acetic and/or hydrochloric acid [9] and 1-nitro-2-dimethylaminopropylene by ammonia and alkylamines (without acid) or arylamines in the presence of an equimolar amount of p-toluenesulfonic acid [10].We have studied the reaction of 1-alkyl-3-alkylaminopyrrole-2,5-diones with arylamines with the aim of preparing 1-alkyl-3-arylaminopyrrole-2,5-diones.It was found that 1-methyl-3-methylaminopyrrole-2,5-dione 1 does not react with aniline at a reagent ratio from 1: 1 to 1: 3 under various conditions (refluxing in methanol, heating at 100-120ºC in DMSO, or at 100ºC without solvent over 5-40 h in the absence or presence of a catalytic or an equimolar amount of acetic acid. By contrast maleimide 1 reacts rapidly with an equimolar amount of the arylamine hydrochlorides 2a-m by heating for 1 h in methanol or DMSO to give good yields of the corresponding 3-arylamino-1-methylpyrrole-2,5-diones 3a-m (Tables 1, 2). In a similar reaction 1-(2-hydroxyethyl)-3-(2-hydroxyethylamino)pyrrole-2,5-dione reacts with p-anisidine hydrochloride to give 1-(2-hydroxyethyl)-3-(p-methoxyphenylamino)pyrrole-2,5-dione (3n) (Tables 1, 2). The reaction of maleimide 1 with an equimolar amount of aniline in the presence of 15 mole % of aniline hydrochloride (refluxing in methanol for 1 h) gave a low yield (5%) of the 1-methyl-3-phenylaminopyrrole-2,5-dione 3a.

Diastereoselective alkylation of prochiral oxonitrile dianions with secondary alkyl halides efficiently installs two contiguous stereogenic centers. The confluence of nucleophilic trajectory and the electrophile chirality causes distinct steric differences that allow efficient discrimination for one of the six possible conformers. Numerous oxonitrile-derived dianions efficiently displace secondary alkyl halides propagating the electrophile chirality to efficiently install two contiguous tertiary centers. The prevalence of chiral, secondary electrophiles makes the interdigitated alkylation of chiral electrophiles a particularly attractive route because the resulting oxonitriles are readily transformed into bioactive heterocycles.

Pyrrole derivatives R 0120Synthesis of 1-Alkyl-3-arylamino-pyrrole-2,5-diones -[via transamination of 3-methylaminopyrroledione (I) or by reaction of arylaminofumarates (VI) with primary amines]. -(CHEPYSHEV*, S. V.; MAZURKEVICH, Y. N.; LEBED', O. S.; PROSYANIK, A. V.; Chem. Heterocycl. Compd. (N. Y.) 43 (2007) 7, 844-849; Ukr. State Chem. Eng. Univ., Dnepropetrovsk 49005, Ukraine; Eng.) -H. Toeppel 12-110

Keywords: 3,3'-bipyrrolyl-2,5,2',5'-tetraone, pyrrole-2,5-dione, benzenehexacarboxylic acid trimethylimide.We have previously shown [1, 2] that the reaction of 1-alkyl-3-alkylaminopyrrole-2,5-diones with the hydrochlorides or 4-tolylsulfonates of primary arylamines with a pKa value from 5.63 (4-aminophenol) to 1.00 (4-nitroaniline) [3] in methanol gives the corresponding 1-alkyl-3-arylaminopyrrole-2,5-diones.Continuing the investigation we have discovered that reaction of 1-methyl-3-methylaminopyrrole-2,5-dione 1 with the weaker bases 2-nitroaniline, 2-bromo-4-nitroaniline, or 2,4-dinitroaniline (with pKa's of -0.25, -1.18 (calculated value), and -4.27 [3]) in the presence of hydrogen chloride (molar ratio of reagents 1:1.2:1 with refluxing over 5 min) did not give the expected 3-arylamino-1-methylpyrrole-2,5-diones. Reaction occurs only in about 50% yield to the benzenehexacarboxylic acid trimethylimide 2 which had been obtained previously in the reaction of N-methyl-5-methyloxazolium methosulfate with potassium oxalate in water [4,5].